Neuroscience

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Posts tagged alzheimer's disease

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Study of Dietary Intervention Examines Proteins in Brain

The lipidation states (or modifications) in certain proteins in the brain that are related to the development of Alzheimer disease appear to differ depending on genotype and cognitive diseases, and levels of these protein and peptides appear to be influenced by diet, according to a report published Online First by JAMA Neurology, a JAMA Network publication.

Sporadic Alzheimer disease (AD) is caused in part by the accumulation of β-amyloid (Αβ) peptides in the brain. These peptides can be bound to lipids or lipid carrier proteins, such as apolipoprotein E (ApoE), or be free in solution (lipid-depleted [LD] Αβ). Levels of LD Αβ are higher in the plasma of adults with AD, but less is known about these peptides in the cerebrospinal fluid (CSF), the authors write in the study background.

Angela J. Hanson, M.D., Veterans Affairs Puget Sound Health Care System and the University of Washington, Seattle, and colleagues studied 20 older adults with normal cognition (average age 69 years) and 27 older adults with amnestic mild cognitive impairment (average age 67 years).

The patients were randomized to a diet high in saturated fat content (45 percent energy from fat, greater than 25 percent saturated fat) with a high glycemic index or a diet low in saturated fat content (25 percent of energy from fat, less than 7 percent saturated fat) with a low glycemic index. The main outcomes the researchers measured were lipid depleted (LD) Αβ42 and Αβ40 and ApoE in cerebrospinal fluid.

Study results indicate that baseline levels of LD Αβ were greater for adults with mild cognitive impairment compared with adults with normal cognition. The authors also note that these findings were more apparent in adults with mild cognitive impairment and the Ɛ4 allele (a risk factor for AD), who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis. Study results indicate that the diet low in saturated fat tended to decrease LD Αβ levels, whereas the diet high in saturated fat increased these fractions.

The authors note the data from their small pilot study need to be replicated in a larger sample before any firm conclusions can be drawn.

“Overall, these results suggest that the lipidation states of apolipoproteins and amyloid peptides might play a role in AD pathological processes and are influenced by APOE genotype and diet,” the study concludes.

Editorial: Food for Thought

In an editorial, Deborah Blacker, M.D., Sc.D., of the Massachusetts General Hospital/Harvard Medical School, Boston, writes: “The article by Hanson and colleagues makes a serious effort to understand whether dietary factors can affect the biology of Alzheimer disease (AD).”

“Hanson et al argue that the changes observed after their two dietary interventions may underlie some of the epidemiologic findings regarding diabetes and other cardiovascular risk factors and risk for AD. The specifics of their model may not capture the real underlying biological effect of these diets, and it is unclear whether the observed changes in the intermediate outcomes would lead to beneficial changes in oligomers or plaque burden, much less to decreased brain atrophy or improved cognition,” she continues.

“At some level, however, the details of the biological model are not critical; the important lesson from the study is that dietary intervention can change brain amyloid chemistry in largely consistent and apparently meaningful ways – in a short period of time. Does this change clinical practice for those advising patients who want to avoid dementia? Probably not, but it adds another small piece to the growing evidence that taking good care of your heart is probably good for your brain too,” Blacker concludes.

(Source: media.jamanetwork.com)

Filed under alzheimer's disease proteins diet amyloid peptides APOE genotype neuroscience science

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Rare genomic mutations found in 10 families with early-onset, familial Alzheimer’s disease Although a family history of Alzheimer’s disease is a primary risk factor for the devastating neurological disorder, mutations in only three genes – the amyloid precursor protein and presenilins 1 and 2 – have been established as causative for inherited, early-onset Alzheimer’s, accounting for about half of such cases. Now Massachusetts General Hospital (MGH) researchers have discovered a type of mutation known as copy-number variants (CNVs) – deletions, duplications, or rearrangements of human genomic DNA – in affected members of 10 families with early-onset Alzheimer’s. Notably, different genomic changes were identified in the Alzheimer’s patients in each family. The study was conducted as part of the Alzheimer’s Genome Project – directed by Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) and a co-discoverer of the first three early-onset genes – and was supported by the Cure Alzheimer’s Fund and the National Institute of Mental Health (NIMH). "We found that the Alzheimer’s-afflicted members of these families had duplications or deletions in genes with important roles in brain function, while their unaffected siblings had unaltered copies of those genes," says Basavaraj Hooli, PhD, of the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, lead author of a report that has been published online in Molecular Psychiatry. “Since our preliminary review of the affected genes has provided strong clues to a range of pathways associated with Alzheimer’s disease and other forms of dementia, we believe that further research into the functional effects of these CNVs will provide new insights into Alzheimer’s pathogenesis.” Hooli is a research fellow in Neurology at Harvard Medical School. Most studies searching for genes contributing to Alzheimer’s risk have looked for variants in a single nucleotide, and while thousands of such changes have been identified, each appears to have a very small impact on disease risk. Recently research has found that CNVs – in which DNA segments of varying lengths are deleted or duplicated – have a greater impact on genomic diversity than do single-nucleotide changes. This led Tanzi and his team to search for large CNVs in affected members of families with inherited Alzheimer’s disease. “These are the first new early-onset familial Alzheimer’s disease gene mutations to be reported since 1995, when we co-discovered the presenilins. As with those original genes, we hope to use the information gained from studies of the new Alzheimer’s mutations to guide the development of novel therapies aimed at preventing and treating this devastating disease.” Tanzi explains. The investigators reviewed genomic data from two sources – the NIMH Alzheimer’s Disease Genetics Initiative and the National Cell Repository for Alzheimer’s Disease – and focused on 261 families with at least one member who developed Alzheimer’s before the age of 65. Using a novel algorithm they had developed for analyzing CNVs, the researchers identified deletions or duplications that appeared only in affected members of these families. Two of these families had CNVs that included the well-established amyloid precursor protein gene, but 10 others were found to have novel Alzheimer’s-associated CNVs, with different gene segments being affected in each family. While none of the novel variants have previously been associated with Alzheimer’s disease, most of them affect genes believed to be essential to normal neuronal function, and several have been previously associated with other forms of dementia. For example, one of the identified CNVs involves deletion of a gene called CHMP2B, mutations of which can cause ALS. In another family, affected members had three copies of the gene MAPT, which encodes the tau protein found in the neurofibrillary tangles characteristic of Alzheimer’s. Mutations in MAPT also cause frontotemporal dementia.  Hooli explains, “Potential clinical application of the findings of this study are not yet clear and require two additional pieces of information: similar studies in larger groups of families with inherited Alzheimer’s to establish the prevalence of these CNVs and whether the presence of one ensures development of the disease, and a better understanding of how these variants affect neuronal pathways leading to the early-onset form of Alzheimer’s disease.” "In a broader sense," Tanzi adds, "the advent of affordable, advanced whole-genome sequencing will lead to the identification of novel, rare mutations that lead to many human disorders. In the future, diagnosis and prognosis may rely more on disease genetics than on traditional laboratory results and behavioral effects. If knowing the exact genetic causes of these disorders leads to more effective and efficient treatment strategies targeted to specific defects, the consequences of this approach would be enormous."

Rare genomic mutations found in 10 families with early-onset, familial Alzheimer’s disease

Although a family history of Alzheimer’s disease is a primary risk factor for the devastating neurological disorder, mutations in only three genes – the amyloid precursor protein and presenilins 1 and 2 – have been established as causative for inherited, early-onset Alzheimer’s, accounting for about half of such cases. Now Massachusetts General Hospital (MGH) researchers have discovered a type of mutation known as copy-number variants (CNVs) – deletions, duplications, or rearrangements of human genomic DNA – in affected members of 10 families with early-onset Alzheimer’s. Notably, different genomic changes were identified in the Alzheimer’s patients in each family.

The study was conducted as part of the Alzheimer’s Genome Project – directed by Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) and a co-discoverer of the first three early-onset genes – and was supported by the Cure Alzheimer’s Fund and the National Institute of Mental Health (NIMH).

"We found that the Alzheimer’s-afflicted members of these families had duplications or deletions in genes with important roles in brain function, while their unaffected siblings had unaltered copies of those genes," says Basavaraj Hooli, PhD, of the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, lead author of a report that has been published online in Molecular Psychiatry. “Since our preliminary review of the affected genes has provided strong clues to a range of pathways associated with Alzheimer’s disease and other forms of dementia, we believe that further research into the functional effects of these CNVs will provide new insights into Alzheimer’s pathogenesis.” Hooli is a research fellow in Neurology at Harvard Medical School.

Most studies searching for genes contributing to Alzheimer’s risk have looked for variants in a single nucleotide, and while thousands of such changes have been identified, each appears to have a very small impact on disease risk. Recently research has found that CNVs – in which DNA segments of varying lengths are deleted or duplicated – have a greater impact on genomic diversity than do single-nucleotide changes. This led Tanzi and his team to search for large CNVs in affected members of families with inherited Alzheimer’s disease. “These are the first new early-onset familial Alzheimer’s disease gene mutations to be reported since 1995, when we co-discovered the presenilins. As with those original genes, we hope to use the information gained from studies of the new Alzheimer’s mutations to guide the development of novel therapies aimed at preventing and treating this devastating disease.” Tanzi explains.

The investigators reviewed genomic data from two sources – the NIMH Alzheimer’s Disease Genetics Initiative and the National Cell Repository for Alzheimer’s Disease – and focused on 261 families with at least one member who developed Alzheimer’s before the age of 65. Using a novel algorithm they had developed for analyzing CNVs, the researchers identified deletions or duplications that appeared only in affected members of these families. Two of these families had CNVs that included the well-established amyloid precursor protein gene, but 10 others were found to have novel Alzheimer’s-associated CNVs, with different gene segments being affected in each family.

While none of the novel variants have previously been associated with Alzheimer’s disease, most of them affect genes believed to be essential to normal neuronal function, and several have been previously associated with other forms of dementia. For example, one of the identified CNVs involves deletion of a gene called CHMP2B, mutations of which can cause ALS. In another family, affected members had three copies of the gene MAPT, which encodes the tau protein found in the neurofibrillary tangles characteristic of Alzheimer’s. Mutations in MAPT also cause frontotemporal dementia.  
Hooli explains, “Potential clinical application of the findings of this study are not yet clear and require two additional pieces of information: similar studies in larger groups of families with inherited Alzheimer’s to establish the prevalence of these CNVs and whether the presence of one ensures development of the disease, and a better understanding of how these variants affect neuronal pathways leading to the early-onset form of Alzheimer’s disease.”

"In a broader sense," Tanzi adds, "the advent of affordable, advanced whole-genome sequencing will lead to the identification of novel, rare mutations that lead to many human disorders. In the future, diagnosis and prognosis may rely more on disease genetics than on traditional laboratory results and behavioral effects. If knowing the exact genetic causes of these disorders leads to more effective and efficient treatment strategies targeted to specific defects, the consequences of this approach would be enormous."

Filed under alzheimer's disease dementia amyloid precursor protein genetics genomics neuroscience science

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Alzheimer’s brain change measured in humans Scientists at Washington University School of Medicine in St. Louis have measured a significant and potentially pivotal difference between the brains of patients with an inherited form of Alzheimer’s disease and healthy family members who do not carry a mutation for the disease. Researchers have known that amyloid beta, a protein fragment, builds up into plaques in the brains of Alzheimer’s patients. They believe the plaques cause the memory loss and other cognitive problems that characterize the disease. Normal brain metabolism produces different forms of amyloid beta. The new study shows that research participants with genetic mutations that cause early-onset Alzheimer’s make about 20 percent more of a specific form of amyloid beta – known as amyloid beta 42 – than family members who do not have the Alzheimer’s mutation. Scientists found another, more surprising difference linked to amyloid beta 42 in mutation carriers: signs that amyloid beta 42 drops out of the cerebrospinal fluid much more quickly than other forms of amyloid beta. This may be because amyloid beta 42 is being deposited on brain amyloid plaques. “These results indicate how much we should target amyloid beta 42 with Alzheimer’s drugs,” said Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology. “We are hopeful that this and other research will lead to preventive therapies to delay or even possibly prevent Alzheimer’s disease.” The study appears June 12 in Science Translational Medicine. In addition to helping develop treatments for inherited Alzheimer’s, investigations of these conditions have helped scientists lay the groundwork for advances in treatment of the much more common sporadic forms of the disease. Three forms account for most of the amyloid beta found in the cerebrospinal fluid: amyloid beta 38, 40 and 42. Earlier studies of the human brain after death and using animal research had suggested that amyloid beta 42 was the most important contributor to Alzheimer’s. The new study not only confirms this connection but also quantifies overproduction of amyloid beta 42 for the first time in living human brains. Bateman, who co-developed a technique that measures the rate at which amyloid beta is produced and cleared from the cerebrospinal fluid, contacted several Washington University colleagues to see if they could develop a way to analyze the types of amyloid beta being produced in the brain. Bateman, metabolism expert Bruce Patterson, PhD, and biomedical engineer Donald Elbert, PhD, created a new mathematical model to describe the production and clearance of amyloid beta. The scientists applied the model to data from 11 research participants with Alzheimer’s mutations and 12 related family members who did not have the genetic errors that cause Alzheimer’s. The model let the scientists compare the production rates of the protein’s different forms, revealing an increase in amyloid beta 42 production in subjects with an Alzheimer’s gene. “Working in isolation, any one of us would likely have gotten the wrong answer, or no answer,” Elbert said. “Bringing our different skill sets together let us tackle a very complex physiological problem.” Scientists are testing the new model on data from approximately 100 Alzheimer’s patients. “We hope that our new insights about the production and clearance of amyloid beta proteins will pave the way for future studies aimed at understanding and altering the metabolic processes that underlie this devastating disease,” Patterson said.

Alzheimer’s brain change measured in humans

Scientists at Washington University School of Medicine in St. Louis have measured a significant and potentially pivotal difference between the brains of patients with an inherited form of Alzheimer’s disease and healthy family members who do not carry a mutation for the disease.

Researchers have known that amyloid beta, a protein fragment, builds up into plaques in the brains of Alzheimer’s patients. They believe the plaques cause the memory loss and other cognitive problems that characterize the disease. Normal brain metabolism produces different forms of amyloid beta.

The new study shows that research participants with genetic mutations that cause early-onset Alzheimer’s make about 20 percent more of a specific form of amyloid beta – known as amyloid beta 42 – than family members who do not have the Alzheimer’s mutation.

Scientists found another, more surprising difference linked to amyloid beta 42 in mutation carriers: signs that amyloid beta 42 drops out of the cerebrospinal fluid much more quickly than other forms of amyloid beta. This may be because amyloid beta 42 is being deposited on brain amyloid plaques.

“These results indicate how much we should target amyloid beta 42 with Alzheimer’s drugs,” said Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology. “We are hopeful that this and other research will lead to preventive therapies to delay or even possibly prevent Alzheimer’s disease.”

The study appears June 12 in Science Translational Medicine.

In addition to helping develop treatments for inherited Alzheimer’s, investigations of these conditions have helped scientists lay the groundwork for advances in treatment of the much more common sporadic forms of the disease.

Three forms account for most of the amyloid beta found in the cerebrospinal fluid: amyloid beta 38, 40 and 42. Earlier studies of the human brain after death and using animal research had suggested that amyloid beta 42 was the most important contributor to Alzheimer’s. The new study not only confirms this connection but also quantifies overproduction of amyloid beta 42 for the first time in living human brains.

Bateman, who co-developed a technique that measures the rate at which amyloid beta is produced and cleared from the cerebrospinal fluid, contacted several Washington University colleagues to see if they could develop a way to analyze the types of amyloid beta being produced in the brain.

Bateman, metabolism expert Bruce Patterson, PhD, and biomedical engineer Donald Elbert, PhD, created a new mathematical model to describe the production and clearance of amyloid beta.

The scientists applied the model to data from 11 research participants with Alzheimer’s mutations and 12 related family members who did not have the genetic errors that cause Alzheimer’s. The model let the scientists compare the production rates of the protein’s different forms, revealing an increase in amyloid beta 42 production in subjects with an Alzheimer’s gene.

“Working in isolation, any one of us would likely have gotten the wrong answer, or no answer,” Elbert said. “Bringing our different skill sets together let us tackle a very complex physiological problem.”

Scientists are testing the new model on data from approximately 100 Alzheimer’s patients.

“We hope that our new insights about the production and clearance of amyloid beta proteins will pave the way for future studies aimed at understanding and altering the metabolic processes that underlie this devastating disease,” Patterson said.

Filed under alzheimer's disease dementia amyloid plaques beta amyloid neuroscience science

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Alzheimer’s and Low Blood Sugar in Diabetes May Trigger a Vicious Cycle A new UC San Francisco-led study looks at the close link between diabetes and dementia, which can create a vicious cycle. Diabetes-associated episodes of low blood sugar may increase the risk of developing dementia, while having dementia or even milder forms of cognitive impairment may increase the risk of experiencing low blood sugar, according to the study published online Monday in JAMA Internal Medicine. Researchers analyzed data from 783 diabetic participants and found that hospitalization for severe hypoglycemia among the diabetic, elderly participants in the study was associated with a doubled risk of developing dementia later. Similarly, study participants with dementia were twice as likely to experience a severe hypoglycemic event. The study results suggest some patients risk entering a downward spiral in which hypoglycemia and cognitive impairment fuel one another, leading to worse health, said Kristine Yaffe, MD, senior author and principal investigator for the study, and a UCSF professor of psychiatry, neurology and epidemiology based at the San Francisco Veterans Affair Medical Center. “Older patients with diabetes may be especially vulnerable to a vicious cycle in which poor diabetes management may lead to cognitive decline and then to even worse diabetes management,” she said. Cognitive Function a Factor in Managing Diabetes The researchers analyzed hospital records of patients from Memphis and Pittsburgh, ages 70 to 79 at the time of enrollment, who participated in the federally funded Health, Aging and Body Composition (Health ABC) study, begun in 1997. The UCSF results are based on an average of 12 years of follow-up study. Participants in the Health ABC study periodically underwent tests to measure cognitive function. Nearly half of participants included in the newly published analysis were black, and the rest were white. None had dementia at the start of the study, and all either had diabetes at the beginning of the study or were diagnosed during the course of the study. “Individuals with dementia or even those with milder forms of cognitive impairment may be less able to effectively manage complex treatment regimens for diabetes and less able to recognize the symptoms of hypoglycemia and to respond appropriately, increasing their risk of severe hypoglycemia,” Yaffe said. “Physicians should take cognitive function into account in managing diabetes in elderly individuals.” Certain medications known to carry a higher risk for hypoglycemia — such as insulin secretagogues and certain sulfonylureas — may be inappropriate for older adults with dementia or who are at risk for cognitive impairment, according to Yaffe. Previous studies in which researchers investigated hypoglycemia and cognitive function have had inconsistent findings. A strength of the current study is that individuals were tracked from baseline over a relatively long time, and the older age of participants may also have been a factor in the highly statistically significant outcome, Yaffe said.

Alzheimer’s and Low Blood Sugar in Diabetes May Trigger a Vicious Cycle

A new UC San Francisco-led study looks at the close link between diabetes and dementia, which can create a vicious cycle.

Diabetes-associated episodes of low blood sugar may increase the risk of developing dementia, while having dementia or even milder forms of cognitive impairment may increase the risk of experiencing low blood sugar, according to the study published online Monday in JAMA Internal Medicine.

Researchers analyzed data from 783 diabetic participants and found that hospitalization for severe hypoglycemia among the diabetic, elderly participants in the study was associated with a doubled risk of developing dementia later. Similarly, study participants with dementia were twice as likely to experience a severe hypoglycemic event.

The study results suggest some patients risk entering a downward spiral in which hypoglycemia and cognitive impairment fuel one another, leading to worse health, said Kristine Yaffe, MD, senior author and principal investigator for the study, and a UCSF professor of psychiatry, neurology and epidemiology based at the San Francisco Veterans Affair Medical Center.

“Older patients with diabetes may be especially vulnerable to a vicious cycle in which poor diabetes management may lead to cognitive decline and then to even worse diabetes management,” she said.

Cognitive Function a Factor in Managing Diabetes

The researchers analyzed hospital records of patients from Memphis and Pittsburgh, ages 70 to 79 at the time of enrollment, who participated in the federally funded Health, Aging and Body Composition (Health ABC) study, begun in 1997. The UCSF results are based on an average of 12 years of follow-up study. Participants in the Health ABC study periodically underwent tests to measure cognitive function.

Nearly half of participants included in the newly published analysis were black, and the rest were white. None had dementia at the start of the study, and all either had diabetes at the beginning of the study or were diagnosed during the course of the study.

“Individuals with dementia or even those with milder forms of cognitive impairment may be less able to effectively manage complex treatment regimens for diabetes and less able to recognize the symptoms of hypoglycemia and to respond appropriately, increasing their risk of severe hypoglycemia,” Yaffe said. “Physicians should take cognitive function into account in managing diabetes in elderly individuals.”

Certain medications known to carry a higher risk for hypoglycemia — such as insulin secretagogues and certain sulfonylureas — may be inappropriate for older adults with dementia or who are at risk for cognitive impairment, according to Yaffe.

Previous studies in which researchers investigated hypoglycemia and cognitive function have had inconsistent findings. A strength of the current study is that individuals were tracked from baseline over a relatively long time, and the older age of participants may also have been a factor in the highly statistically significant outcome, Yaffe said.

Filed under alzheimer's disease dementia diabetes cognitive function cognitive impairment insulin neuroscience science

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China’s Alzheimer’s time bomb revealed

In 2010, China had more people living with Alzheimer’s disease than any other country in the world – and twice as many cases of Alzheimer’s and other kinds of dementia as the World Health Organization thought.

image

Cases of all kinds of age-related dementia in the country rose from 3.7 million in 1990 to 9.2 million in 2010. This is the finding of the first comprehensive analysis of Chinese epidemiological research, made possible by the recent digitisation of Chinese-language research papers. Previous estimates, based on English-language papers, seem to have under-reported the number of cases by half.

"We are now only beginning to comprehend the enormous value in this ‘parallel universe’ of information," says Igor Rutan of the University of Edinburgh, UK, who was part of the team that carried out the research.

The figures are bad news for a country where 90 per cent of the elderly must be cared for by their families – old people who still have family members living are not allowed to be admitted to a nursing home – even as widespread migration to cities has disrupted the traditional family structure.

Population bulge

The findings are a reflection of China’s ageing population, and its policies.

As countries modernise, death rates fall, and later on birth rates fall as more people take up birth control. Between the two events, though, there is a “bulge” of births, the source of the modern world’s population explosion. Eventually birth and death rates roughly equalise, but the birth bulge remains as an age bulge in the population.

This reached an extreme in China, where a surge in births in the 1950s and 1960s was followed by plummeting birth rates in the 1970s, later reinforced by China’s one-child policy. “Family planning policy means China is becoming an ageing country much faster than other middle-income countries such as India,” says co-author Wei Wang of Edith Cowan University in Perth, Australia.

In its youth, the bulge underpinned China’s economic development. But by 2033, it is predicted that working-age people will be outnumbered by dependents, mostly the elderly.

The new research shows that they will need more care than China was expecting. Dementia rises in an ageing population: cases increased from 4.9 to 6.3 million in the greying European Union between 2004 and 2010.

Unhealthy lifestyle

"The rates in China are similar or even higher than rates in Europe and the US," says Wang.

And they are rising. In 1990, the team estimates, 1.8 per cent of Chinese aged 65 to 69, and 42.1 per cent aged 95 to 99, had dementia. In 2010 those figures were 2.6 and 60.5 per cent, respectively. If similar rates hold in other middle-income countries, there might be 20 per cent more cases of Alzheimer’s worldwide – five million more – than now estimated, the authors calculate.

The increase in China might reflect better diagnosis, but an urbanising lifestyle could also be causing more dementia. “Obesity, diabetes and suboptimal health contribute,” says Wang.

Martin Prince of King’s College London, who is organising another survey for dementia in China, says that if midlife obesity is a risk factor for dementia, then future rates in China could be 20 per cent higher than estimated.

(Source: newscientist.com)

Filed under alzheimer's disease dementia China aging one-child policy lifestyle psychology neuroscience science

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Alzheimer’s, Schizophrenia, and Autism Now Can Be Studied With Mature Brain Cells Reprogrammed from Skin Cells Difficult-to-study diseases such as Alzheimer’s, schizophrenia, and autism now can be probed more safely and effectively thanks to an innovative new method for obtaining mature brain cells called neurons from reprogrammed skin cells. According to Gong Chen, the Verne M. Willaman Chair in Life Sciences and professor of biology at Penn State University and the leader of the research team, “the most exciting part of this research is that it offers the promise of direct disease modeling, allowing for the creation, in a Petri dish, of mature human neurons that behave a lot like neurons that grow naturally in the human brain.” Chen added that the method could lead to customized treatments for individual patients based on their own genetic and cellular information. The research will be published in the journal Stem Cell Research. "Obviously, we don’t want to remove someone’s brain cells to experiment on, so recreating the patient’s brain cells in a Petri dish is the next best thing for research purposes and drug screening," Chen said. Chen explained that, in earlier work, scientists had found a way to reprogram skin cells from patients to become unspecialized or undifferentiated pluripotent stem cells (iPSCs). "A pluripotent stem cell is a kind of blank slate," Chen explained. "During development, such stem cells differentiate into many diverse, specialized cell types, such as a muscle cell, a brain cell, or a blood cell. So, after generating iPSCs from skin cells, researchers then can culture them to become brain cells, or neurons, which can be studied safely in a Petri dish." Now, in their new research, Chen and his team have found a way to differentiate iPSCs into mature human neurons much more effectively, generating cells that behave similarly to neurons in the brain. Chen explained that, in their natural environment, neurons are always found in close proximity to star-shaped cells called astrocytes, which are abundant in the brain and help neurons to function properly. “Because neurons are adjacent to astrocytes in the brain, we predicted that this direct physical contact might be an integral part of neuronal growth and health,” Chen explained. To test this hypothesis, Chen and his colleagues began by culturing iPSC-derived neural stem cells, which are stem cells that have the potential to become neurons. These cells were cultured on top of a one-cell-thick layer of astrocytes so that the two cell types were physically touching each other. "We found that these neural stem cells cultured on astrocytes differentiated into mature neurons much more effectively," Chen said, contrasting them with other neural stem cells that were cultured alone in a Petri dish. "It was almost as if the astrocytes were cheering the stem cells on, telling them what to do, and helping them fulfill their destiny to become neurons." To demonstrate the superiority of the neurons grown next to astrocytes, Chen and his co-authors used an electrophysiology recording technique to show that the cells grown on astrocytes had many more synaptic events — signals sent out from one nerve cell to the others. In another experiment, after growing the neural stem cells next to astrocytes for just one week, the researchers showed that the newly differentiated neurons start to fire action potentials — the rapid electrical excitation signal that occurs in all neurons in the brain. In a final test, the team members added human neural stem cells to a mixture with mouse neurons. “We found that, after just one week, there was a lot of ‘cross-talk’ between the mouse neurons and the human neurons,” Chen said. He explained that “cross-talk” occurs when one neuron contacts its neighbors and releases a chemical called a neurotransmitter to modulate its neighbor’s activity. "Previous researchers could only obtain brain cells from deceased patients who had suffered from diseases such as Alzheimer’s, schizophrenia, and autism," Chen said. "Now, researchers can take skin cells from living patients — a safe and minimally invasive procedure — and convert them into brain cells that mimic the activity of the patient’s own brain cells." Chen added that, by using this method, researchers also can figure out how a particular drug will affect a particular patient’s own brain cells, without needing the patient to try the drug — eliminating the risk of serious side effects. "The patient can be his or her own guinea pig for the design of his or her own treatment, without having to be experimented on directly," Chen said.

Alzheimer’s, Schizophrenia, and Autism Now Can Be Studied With Mature Brain Cells Reprogrammed from Skin Cells

Difficult-to-study diseases such as Alzheimer’s, schizophrenia, and autism now can be probed more safely and effectively thanks to an innovative new method for obtaining mature brain cells called neurons from reprogrammed skin cells. According to Gong Chen, the Verne M. Willaman Chair in Life Sciences and professor of biology at Penn State University and the leader of the research team, “the most exciting part of this research is that it offers the promise of direct disease modeling, allowing for the creation, in a Petri dish, of mature human neurons that behave a lot like neurons that grow naturally in the human brain.” Chen added that the method could lead to customized treatments for individual patients based on their own genetic and cellular information. The research will be published in the journal Stem Cell Research.

"Obviously, we don’t want to remove someone’s brain cells to experiment on, so recreating the patient’s brain cells in a Petri dish is the next best thing for research purposes and drug screening," Chen said. Chen explained that, in earlier work, scientists had found a way to reprogram skin cells from patients to become unspecialized or undifferentiated pluripotent stem cells (iPSCs). "A pluripotent stem cell is a kind of blank slate," Chen explained. "During development, such stem cells differentiate into many diverse, specialized cell types, such as a muscle cell, a brain cell, or a blood cell. So, after generating iPSCs from skin cells, researchers then can culture them to become brain cells, or neurons, which can be studied safely in a Petri dish."

Now, in their new research, Chen and his team have found a way to differentiate iPSCs into mature human neurons much more effectively, generating cells that behave similarly to neurons in the brain. Chen explained that, in their natural environment, neurons are always found in close proximity to star-shaped cells called astrocytes, which are abundant in the brain and help neurons to function properly. “Because neurons are adjacent to astrocytes in the brain, we predicted that this direct physical contact might be an integral part of neuronal growth and health,” Chen explained.

To test this hypothesis, Chen and his colleagues began by culturing iPSC-derived neural stem cells, which are stem cells that have the potential to become neurons. These cells were cultured on top of a one-cell-thick layer of astrocytes so that the two cell types were physically touching each other.

"We found that these neural stem cells cultured on astrocytes differentiated into mature neurons much more effectively," Chen said, contrasting them with other neural stem cells that were cultured alone in a Petri dish. "It was almost as if the astrocytes were cheering the stem cells on, telling them what to do, and helping them fulfill their destiny to become neurons."

To demonstrate the superiority of the neurons grown next to astrocytes, Chen and his co-authors used an electrophysiology recording technique to show that the cells grown on astrocytes had many more synaptic events — signals sent out from one nerve cell to the others. In another experiment, after growing the neural stem cells next to astrocytes for just one week, the researchers showed that the newly differentiated neurons start to fire action potentials — the rapid electrical excitation signal that occurs in all neurons in the brain. In a final test, the team members added human neural stem cells to a mixture with mouse neurons. “We found that, after just one week, there was a lot of ‘cross-talk’ between the mouse neurons and the human neurons,” Chen said. He explained that “cross-talk” occurs when one neuron contacts its neighbors and releases a chemical called a neurotransmitter to modulate its neighbor’s activity.

"Previous researchers could only obtain brain cells from deceased patients who had suffered from diseases such as Alzheimer’s, schizophrenia, and autism," Chen said. "Now, researchers can take skin cells from living patients — a safe and minimally invasive procedure — and convert them into brain cells that mimic the activity of the patient’s own brain cells." Chen added that, by using this method, researchers also can figure out how a particular drug will affect a particular patient’s own brain cells, without needing the patient to try the drug — eliminating the risk of serious side effects. "The patient can be his or her own guinea pig for the design of his or her own treatment, without having to be experimented on directly," Chen said.

Filed under alzheimer's disease autism schizophrenia astrocytes stem cells neurons neuroscience science

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Balancing mitochondrial dynamics in Alzheimer’s disease Many diseases are multifactorial and can not be understood by simple molecular associations alone. Alzheimer’s disease (AD) is associated with toxic transformations in two classes of protein,amyloid beta and tau, but they do not explain the full underlying pathology. On the cellular scale, much of the real-time morphological changes in neurons can be attributed to their underlying mitochondrial dynamics—namely fission, fusion, and the motions between these events. Last year, researchers from Harvard Medical School made the intriguing discovery that alterations in tau could lead to a doubling in the length of mitochondria. This week, they published a review article in Trends in Neuroscience, in which they seek to explain the primary features of AD in terms of mitochondrial dynamics. Together with a collaborator from the Queensland Brain Institute, the Harvard researchers arrive at the conclusion that, like many other neurological diseases, AD is fundamentally an energy problem. While some proteins, like APOE-ɛ4 can predispose one to AD, point defects in individual proteins can not account for AD in the same way that a single alteration in hemoglobin leads to sickle cell disease. Attempts to assign casual relations to the complex interactions of tau or amyloid, with hundreds of other proteins inside neurons have frequently served to cloud, rather than simplify the AD story. In years gone by, it was possible to publish a paper about how phosphorylation at certain sites on proteins, like tau, could lead to any number of downstream events. Tau is one of many proteins that control the assembly and stability of microtubules, critical structures that are among those compromised in AD. The problem now, is that we know tau comes in so many flavors—it is a big family of different isoforms with different properties depending on how they are processed. As far as simple phosphorylation, tau has been found to have 79 potential sites, with at least 30 of them normally phosphorylated. A welcome simplification to this situation of compounding molecular complexity, is that many pathways converge onto convenient pre-existing packets of time, space, and predictable molecular structure—the mitochondria. As opposed to massive cell-wide molecular accounting, describing a few sub-cellular morphological features may be a more tractable approach not only to capture disease etiology, but perhaps to treat it. To this end, the researchers apply existing knowledge regarding some of the molecular players in AD, to a few of the well-established control points in mitochondrial dynamics. State transitions between fission and fusion are, at the moment at least, characterized by only a small handful of proteins. This simple formula might be prescribed as the following: molecular pathway locally effects the organelle dynamics, then, the dynamic behavior of organelle accounts for the disease. The imposition of this middleman can potentially simplify much of the vast body of fact and conjecture associated with the disease. The elongation of mitochondria by tau can be caused by increasing fusion, decreasing fission, or both. One function of tau is to stabilize F-actin networks which prevents a key fission protein from ever reaching the mitochondria. Elongated mitochondria do not necessarily cause AD. In fact, amyloid beta, which is concentrated inside mitochondria, has been shown to cause increased fission and decreased fusion. When the balance between fission and fusion is pushed too far in either direction, the result is bad news for neurons. If there are defects in the transport of mitochondria, as seems to be the case in many neurological diseases, their redistribution is unable to compensate for this loss of balance. Specific disease-associated isoforms and phosphorylation states of tau can lead to AD through the loss of mitochondria in axons. In studies of AD tissue, mitochondria have been found to be preferentially redistributed to the soma. These selective localizations can take place quickly, and are therefore difficult to quantify except by live videomicroscopy. In synapses, the mitochondria have been observed to be longer lived, and to play a more critical role in calcium regulation then those elsewhere. Disruption in the normal handling of calcium has been attributed to many aspects of AD, particularly synaptic pathology. The canonical dogma that action potentials lead to vesicle fusion and transmitter release exclusively through the entry of extracellular calcium has recently been enhanced with the understanding that mitochondria contribute significantly to the synaptic calcium cycle. While mitochondria clearly do not depolarize as rapidly as whole spiking cells,(generally when mitochondria are depolarized there is some problem) their calcium transporters operate quickly to mop up and redistribute calcium. To say that mitochondria might single-handedly initiate vesicle fusion, or for that matter minipotentials or full-blown spikes, would await future experimental corroboration. Countless scores of papers over the years have attempted to make sense of the myriad synaptic pathways underlying memory and LTP. They might be better understood when mitochondria are viewed as the primary authors of synaptic vesicle release probability, and by implication, “spontaneous” release (vesicle fusion in the absence of a spike). As in disease states, specific pathways, structures and organelles have significant roles to play in many aspects of brain function—but causally relating the motions and dynamics of mitochondria to these phenomena now gives the broadest interpretive power.

Balancing mitochondrial dynamics in Alzheimer’s disease

Many diseases are multifactorial and can not be understood by simple molecular associations alone. Alzheimer’s disease (AD) is associated with toxic transformations in two classes of protein,amyloid beta and tau, but they do not explain the full underlying pathology. On the cellular scale, much of the real-time morphological changes in neurons can be attributed to their underlying mitochondrial dynamics—namely fission, fusion, and the motions between these events. Last year, researchers from Harvard Medical School made the intriguing discovery that alterations in tau could lead to a doubling in the length of mitochondria. This week, they published a review article in Trends in Neuroscience, in which they seek to explain the primary features of AD in terms of mitochondrial dynamics.

Together with a collaborator from the Queensland Brain Institute, the Harvard researchers arrive at the conclusion that, like many other neurological diseases, AD is fundamentally an energy problem. While some proteins, like APOE-ɛ4 can predispose one to AD, point defects in individual proteins can not account for AD in the same way that a single alteration in hemoglobin leads to sickle cell disease. Attempts to assign casual relations to the complex interactions of tau or amyloid, with hundreds of other proteins inside neurons have frequently served to cloud, rather than simplify the AD story.

In years gone by, it was possible to publish a paper about how phosphorylation at certain sites on proteins, like tau, could lead to any number of downstream events. Tau is one of many proteins that control the assembly and stability of microtubules, critical structures that are among those compromised in AD. The problem now, is that we know tau comes in so many flavors—it is a big family of different isoforms with different properties depending on how they are processed. As far as simple phosphorylation, tau has been found to have 79 potential sites, with at least 30 of them normally phosphorylated.

A welcome simplification to this situation of compounding molecular complexity, is that many pathways converge onto convenient pre-existing packets of time, space, and predictable molecular structure—the mitochondria. As opposed to massive cell-wide molecular accounting, describing a few sub-cellular morphological features may be a more tractable approach not only to capture disease etiology, but perhaps to treat it.

To this end, the researchers apply existing knowledge regarding some of the molecular players in AD, to a few of the well-established control points in mitochondrial dynamics. State transitions between fission and fusion are, at the moment at least, characterized by only a small handful of proteins. This simple formula might be prescribed as the following: molecular pathway locally effects the organelle dynamics, then, the dynamic behavior of organelle accounts for the disease. The imposition of this middleman can potentially simplify much of the vast body of fact and conjecture associated with the disease.

The elongation of mitochondria by tau can be caused by increasing fusion, decreasing fission, or both. One function of tau is to stabilize F-actin networks which prevents a key fission protein from ever reaching the mitochondria. Elongated mitochondria do not necessarily cause AD. In fact, amyloid beta, which is concentrated inside mitochondria, has been shown to cause increased fission and decreased fusion. When the balance between fission and fusion is pushed too far in either direction, the result is bad news for neurons. If there are defects in the transport of mitochondria, as seems to be the case in many neurological diseases, their redistribution is unable to compensate for this loss of balance.

Specific disease-associated isoforms and phosphorylation states of tau can lead to AD through the loss of mitochondria in axons. In studies of AD tissue, mitochondria have been found to be preferentially redistributed to the soma. These selective localizations can take place quickly, and are therefore difficult to quantify except by live videomicroscopy. In synapses, the mitochondria have been observed to be longer lived, and to play a more critical role in calcium regulation then those elsewhere. Disruption in the normal handling of calcium has been attributed to many aspects of AD, particularly synaptic pathology.

The canonical dogma that action potentials lead to vesicle fusion and transmitter release exclusively through the entry of extracellular calcium has recently been enhanced with the understanding that mitochondria contribute significantly to the synaptic calcium cycle. While mitochondria clearly do not depolarize as rapidly as whole spiking cells,(generally when mitochondria are depolarized there is some problem) their calcium transporters operate quickly to mop up and redistribute calcium. To say that mitochondria might single-handedly initiate vesicle fusion, or for that matter minipotentials or full-blown spikes, would await future experimental corroboration.

Countless scores of papers over the years have attempted to make sense of the myriad synaptic pathways underlying memory and LTP. They might be better understood when mitochondria are viewed as the primary authors of synaptic vesicle release probability, and by implication, “spontaneous” release (vesicle fusion in the absence of a spike). As in disease states, specific pathways, structures and organelles have significant roles to play in many aspects of brain function—but causally relating the motions and dynamics of mitochondria to these phenomena now gives the broadest interpretive power.

Filed under alzheimer's disease mitochondria proteins phosphorylation beta amyloid neuroscience science

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PET Finds Increased Cognitive Reserve Levels in Highly Educated Pre-Alzheimer’s Patients

Highly educated individuals with mild cognitive impairment that later progressed to Alzheimer’s disease cope better with the disease than individuals with a lower level of education in the same situation, according to research published in the June issue of The Journal of Nuclear Medicine. In the study “Metabolic Networks Underlying Cognitive Reserve in Prodromal Alzheimer Disease: A European Alzheimer Disease Consortium Project,”neural reserve and neural compensation were both shown to play a role in determining cognitive reserve, as evidenced by positron emission tomography (PET).

Cognitive reserve refers to the hypothesized capacity of an adult brain to cope with brain damage in order to maintain a relatively preserved functional level. Understanding the brain adaptation mechanisms underlying this process remains a critical question, and researchers of this study sought to investigate the metabolic basis of cognitive reserve in individuals with higher (more than 12 years) and lower (less than 12 years) levels of education who had mild cognitive impairment that progressed to Alzheimer’s disease, also known as prodromal Alzheimer’s disease.

“This study provides new insight into the functional mechanisms that mediate the cognitive reserve phenomenon in the early stages of Alzheimer’s disease,” said Silvia Morbelli, MD, lead author of the study.  “A crucial role of the dorso-lateral prefrontal cortex was highlighted by demonstrating that this region is involved in a wide fronto-temporal and limbic functional network in patients with Alzheimer’s disease and high education, but not in poorly educated Alzheimer’s disease patients.”

In the study, 64 patients with prodromal Alzheimer’s disease and 90 control subjects—coming from the brain PET project (chaired by Flavio Nobili, MD, in Genoa, Italy) of the European Alzheimer Disease Consortium—underwentbrain 18F-FDG PET scans. Individuals were divided into a subgroup with a low level of education (42 controls and 36 prodromal Alzheimer’s disease patients) and a highly educated subgroup (40 controls and 28 prodromal Alzheimer’s disease patients). Brain metabolism was compared between education-matched groups of patients and controls, and then between highly and poorly educated prodromal Alzheimer’s disease patients.

Higher metabolic activity was shown in the dorso-lateral prefrontal cortex for prodromal Alzheimer’s disease patients. More extended and significant correlations of metabolism within the right dorso-lateral prefrontal cortex and other brain regions were found with highly educated than less educated prodromal Alzheimer’s disease patients or even highly educated controls.

This result suggests that neural reserve and neural compensation are activated in highly educated prodromal Alzheimer’s disease patients. Researchers concluded that evaluation of the implication of metabolic connectivity in cognitive reserve further confirms that adding a comprehensive evaluation of resting 18F-FDG PET brain distribution to standard inspection may allow a more complete comprehension of Alzheimer’s disease pathophysiology and possibly may increase 18F-FDG PET diagnostic sensitivity.

“This work supports the notion that employing the brain in complex tasks and developing our own education may help in forming stronger ‘defenses’ against cognitive deterioration once Alzheimer knocks at our door,” noted Morbelli.“It’s possible that, in the future, a combined approach evaluating resting metabolic connectivity and cognitive performance can be used on an individual basis to better predict cognitive decline or response to disease-modifying therapy.”

(Source: interactive.snm.org)

Filed under cognitive impairment alzheimer's disease cognitive reserve PET prodromal alzheimer’s disease education neuroscience science

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Menzies’ Alzheimer’s disease research gains momentum

New research focuses on brain protein thought to be bad

image

Research conducted by Menzies Research Institute Tasmania, an institute of the University of Tasmania, is shedding new light on the biology of Alzheimer’s disease, in particular a protein in the brain that is indirectly responsible for causing Alzheimer’s disease.

Dementia is on the rise in Australia. There will be 75,000 baby boomers with dementia by 2020 and dementia will be the third largest source of health and residential care costs by 2030.*

Approximately 278,700 Australians were living with dementia in 2012. Without a medical breakthrough, the number of people with dementia in Australia is expected to be around 942,620 by 2050.*

Tasmania had over 7,000 people with dementia in 2012; this is projected to increase to 20,650 people by 2050.*

A brain protein known as the amyloid precursor protein (APP) has previously been considered to be mostly bad, in the sense that APP is indirectly responsible for causing Alzheimer’s disease.

Specifically, APP breaks down in the brain to produce a protein called Abeta, which is the direct cause of the disease. However, Menzies researchers have recently discovered that APP has a positive function.

Senior member of Menzies, Professor David Small, said the study discovered that APP is responsible for the growth of new neurons (nerve cells) in the brain.

"In addition to its role in causing Alzheimer’s disease, APP may also be part of a solution to the disease," Professor Small said.

"We may be able to use APP to encourage the brain to replace damaged neurons.

"Dissecting out the yin and yang of APP’s actions may be a key to the treatment of Alzheimer’s disease as well as a number of other similar diseases.

Our recent findings already present us with several avenues for developing new treatment strategies,” he said.

The study was recently published in the prestigious journal, Journal of Biological Chemistry.

(Source: utas.edu.au)

Filed under alzheimer's disease dementia amyloid precursor protein abeta stem cells neurogenesis neuroscience science

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Preventing ‘traffic jams’ in brain cells Imagine if you could open up your brain and look inside. What you would see is a network of nerve cells called neurons, each with its own internal highway system for transporting essential materials between different parts of the cell. When this biological machinery is operating smoothly, tiny motor proteins ferry precious cargo up and down each neuron along thread-like roadways called microtubule tracks. Brain cells are able to receive information, make internal repairs and send instructions to the body, telling the fingers to flex or the toes to curl. But when the neuron gets blocked, this delicate harmony deteriorates. One result: diseases like Alzheimer’s. Understanding such blockages and how traffic should flow normally in healthy brain cells could offer hope to people with neurodegenerative diseases. Toward that end, a research team led by University at Buffalo biologist Shermali Gunawardena, PhD, has shown that the protein presenilin plays an important role in controlling neuronal traffic on microtubule highways, a novel function that previously was unknown. The research results were published online on May 24 in the journal Human Molecular Genetics. Gunawardena’s co-authors are Ge Yang of Carnegie Mellon University and Lawrence S. B. Goldstein of the Howard Hughes Medical Institute and the University of California, San Diego. Inside the nerves of fruit fly larvae, presenilin helped to control the speed at which molecular motors called kinesins and dyneins moved along neurons. When the scientists halved the amount of presenilin present in the highway system, the motors moved faster; they paused fewer times and their pauses were shorter. Given this data, Gunawardena thinks that tweaking presenilin levels may be one way to free up traffic and prevent dangerous neuronal blockages in patients with Alzheimer’s disease. “Our major discovery is that presenilin has a novel role, which is to control the movement of motor proteins along neuronal highways,” said Gunawardena, an assistant professor of biological sciences. “If this regulation/control is lost, then things can go wrong. This is the first time a protein that functions as a controller of motors has been reported. “In Alzheimer’s disease, transport defects occur well before symptoms, such as cell death and amyloid plaques, are seen in post-mortem brains,” she added. “As a result, developing therapeutics targeted to defects in neuronal transport would be a useful way to attack the problem early.” The findings are particularly intriguing because scientists have known for several years that presenilin is involved in Alzheimer’s disease. Presenilin rides along neuronal highways in tiny organic bubbles called vesicles that sit atop the kinesin and dynein motors, and also contain a second protein called the amyloid precursor protein (APP). Presenilin participates in cutting APP into pieces called amyloid beta, which build up to form amyloid plaques in patients with Alzheimer’s disease. Such buildups can lead to cell death by preventing the transport of essential materials—like proteins needed for cell repair—along neurons. The findings of the new study mean that presenilin may contribute to Alzheimer’s disease in at least two ways: not just by cleaving APP, but also by regulating the speed of the molecular motors that carry APP along neuronal highways. “More than 150 mutations in presenilin have been identified in Alzheimer’s disease,” Gunawardena said. “Thus, understanding its function is important to understanding what goes wrong in Alzheimer’s disease.” To track the movement of the kinesins and dyneins, the team tagged their cargo with a yellow fluorescent protein. This enabled the scientists to view the molecular motors chugging along inside the neuron under a microscope in a living animal. A special computer program then analyzed the motors’ paths, revealing more details about the nature of their movement and how often they paused.

Preventing ‘traffic jams’ in brain cells

Imagine if you could open up your brain and look inside.

What you would see is a network of nerve cells called neurons, each with its own internal highway system for transporting essential materials between different parts of the cell.

When this biological machinery is operating smoothly, tiny motor proteins ferry precious cargo up and down each neuron along thread-like roadways called microtubule tracks. Brain cells are able to receive information, make internal repairs and send instructions to the body, telling the fingers to flex or the toes to curl.

But when the neuron gets blocked, this delicate harmony deteriorates. One result: diseases like Alzheimer’s.

Understanding such blockages and how traffic should flow normally in healthy brain cells could offer hope to people with neurodegenerative diseases.

Toward that end, a research team led by University at Buffalo biologist Shermali Gunawardena, PhD, has shown that the protein presenilin plays an important role in controlling neuronal traffic on microtubule highways, a novel function that previously was unknown.

The research results were published online on May 24 in the journal Human Molecular Genetics. Gunawardena’s co-authors are Ge Yang of Carnegie Mellon University and Lawrence S. B. Goldstein of the Howard Hughes Medical Institute and the University of California, San Diego.

Inside the nerves of fruit fly larvae, presenilin helped to control the speed at which molecular motors called kinesins and dyneins moved along neurons. When the scientists halved the amount of presenilin present in the highway system, the motors moved faster; they paused fewer times and their pauses were shorter.

Given this data, Gunawardena thinks that tweaking presenilin levels may be one way to free up traffic and prevent dangerous neuronal blockages in patients with Alzheimer’s disease.

“Our major discovery is that presenilin has a novel role, which is to control the movement of motor proteins along neuronal highways,” said Gunawardena, an assistant professor of biological sciences. “If this regulation/control is lost, then things can go wrong. This is the first time a protein that functions as a controller of motors has been reported.

“In Alzheimer’s disease, transport defects occur well before symptoms, such as cell death and amyloid plaques, are seen in post-mortem brains,” she added. “As a result, developing therapeutics targeted to defects in neuronal transport would be a useful way to attack the problem early.”

The findings are particularly intriguing because scientists have known for several years that presenilin is involved in Alzheimer’s disease.

Presenilin rides along neuronal highways in tiny organic bubbles called vesicles that sit atop the kinesin and dynein motors, and also contain a second protein called the amyloid precursor protein (APP). Presenilin participates in cutting APP into pieces called amyloid beta, which build up to form amyloid plaques in patients with Alzheimer’s disease.

Such buildups can lead to cell death by preventing the transport of essential materials—like proteins needed for cell repair—along neurons.

The findings of the new study mean that presenilin may contribute to Alzheimer’s disease in at least two ways: not just by cleaving APP, but also by regulating the speed of the molecular motors that carry APP along neuronal highways.

“More than 150 mutations in presenilin have been identified in Alzheimer’s disease,” Gunawardena said. “Thus, understanding its function is important to understanding what goes wrong in Alzheimer’s disease.”

To track the movement of the kinesins and dyneins, the team tagged their cargo with a yellow fluorescent protein. This enabled the scientists to view the molecular motors chugging along inside the neuron under a microscope in a living animal. A special computer program then analyzed the motors’ paths, revealing more details about the nature of their movement and how often they paused.

Filed under nerve cells alzheimer's disease protein presenilin fruit fly motor proteins neuroscience science

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