Posts tagged amyloid precursor protein
Articles and news from the latest research reports.
How Alzheimer’s could occur
Protein spheres in the nucleus give wrong signal for cell division
RUB researchers develop new hypothesis for the degeneration of nerve cells
A new hypothesis has been developed by researchers in Bochum on how Alzheimer’s disease could occur. They analysed the interaction of the proteins FE65 and BLM that regulate cell division. In the cell culture model, they discovered spherical structures in the nucleus that contained FE65 and BLM. The interaction of the proteins triggered a wrong signal for cell division. This may explain the degeneration and death of nerve cells in Alzheimer’s patients. The team led by Dr. Thorsten Müller and Prof. Dr. Katrin Marcus from the Department of Functional Proteomics in cooperation with the RUB’s Medical Proteome Centre headed by Prof. Helmut E. Meyer reported on the results in the “Journal of Cell Science”.
Components of spherical structures in the nucleus identified
The so-called amyloid precursor protein APP is central to Alzheimer’s disease. It spans the cell membrane, and its cleavage products are linked to protein deposits that form in Alzheimer patients outside the nerve cells. APP anchors the protein FE65 to the membrane, which was the focus of the current study. FE65 can migrate into the nucleus, where it plays a role in DNA replication and repair. Based on cells grown in the laboratory, the team led by Dr. Müller established that FE65 can unite with other proteins in the cell nucleus to form spherical structures, so-called “nuclear spheres”. Video microscopy showed that these ring-like structures merge with each other and can thus grow. “By using a special cell culture model, we were able to identify additional components of these spheres”, says Andreas Schrötter, PhD student in the working group Morbus Alzheimer at the Institute for Functional Proteomics. Among other things, the scientists found the protein BLM, which is known from Bloom’s syndrome – an extremely rare hereditary disease, which is associated with dwarfism, immunodeficiency, and an increased risk of cancer. BLM is involved in DNA replication and repair in the nucleus.
The amount of FE65 determines the amount of BLM in the cell nucleus
Müller’s team took a closer look at the function of FE65. By means of genetic manipulation, the researchers generated cell cultures, in which the FE65-production was reduced. A smaller amount of FE65 thus generated a smaller amount of the protein BLM in the nucleus. Instead, BLM collected in another area of the cell, the endoplasmic reticulum. In addition, the researchers found a lower rate of DNA replication in the genetically modified cells. In this way, FE65 influences the replication of the genetic material via the BLM protein. When the researchers cranked up the FE65-production again, the amount of BLM in the nucleus also increased again.
FE65 as a possible trigger for Alzheimer’s
In patients with Alzheimer’s disease, the protein APP, an interaction partner of FE65, changes. The interaction of the two molecules is important for the transport of FE65 into the nucleus, where it regulates cell division in combination with BLM. Müller’s team assumes that the altered APP-FE65 interaction mistakenly sends the cells the signal to divide. Since nerve cells normally cannot divide, they degenerate instead and die. “This hypothesis, which we pursue in the working group Morbus Alzheimer, also delivers new starting points for potential therapies, which are urgently needed for Alzheimer’s disease,” says Dr. Mueller. In the future, the team will also investigate whether and how the amount of BLM is altered in Alzheimer’s patients compared to healthy subjects.
(Source: alphagalileo.org)
Researchers create next-generation Alzheimer’s disease model
A new genetically engineered lab rat that has the full array of brain changes associated with Alzheimer’s disease supports the idea that increases in a molecule called beta-amyloid in the brain causes the disease, according to a study, published in the Journal of Neuroscience. The study was supported by the National Institutes of Health.
"We believe the rats will be an excellent, stringent pre-clinical model for testing experimental Alzheimer’s disease therapeutics,” said Terrence Town, Ph.D., the study’s senior author and a professor in the Department of Physiology & Biophysics in the Zilkha Neurogenetic Institute at the University of Southern California Keck School of Medicine, Los Angeles.
Alzheimer’s is an age-related brain disorder that gradually destroys a person’s memory, thinking, and the ability to carry out even the simplest tasks. Affecting at least 5.1 million Americans, the disease is the most common form of dementia in the United States. Pathological hallmarks of Alzheimer’s brains include abnormal levels of beta-amyloid protein that form amyloid plaques; tau proteins that clump together inside neurons and form neurofibrillary tangles; and neuron loss.
Additionally, glial cells—which normally support, protect, or nourish nerve cells—are overactivated in Alzheimer’s.
Plaque-forming beta-amyloid molecules are derived from a larger protein called amyloid precursor protein (APP). One hypothesis states that increases in beta-amyloid initiate brain degeneration. Genetic studies on familial forms of Alzheimer’s support the hypothesis by linking the disease to mutations in APP, and to presenilin 1, a protein thought to be involved in the production beta-amyloid.
Researchers often use rodents to study diseases. However, previous studies on transgenic mice and rats that have the APP and presenilin 1 mutations only partially reproduce the problems caused by Alzheimer’s. The animals have memory problems and many plaques but none of the other hallmarks, especially neurofibrillary tangles and neuron loss.
To address this issue, Dr. Town and his colleagues decided to work with a certain strain of rats.
“We focused on Fischer 344 rats because their brains develop many of the age-related features seen in humans,” said Dr. Town, who conducted the study while working as a professor of Biomedical Sciences at Cedars-Sinai Medical Center and David Geffen School of Medicine at the University of California, Los Angeles.
The rats were engineered to have the mutant APP and presenilin 1 genes, which are known to play a role in the rare, early-onset form of Alzheimer’s. Behavioral studies showed that the rats developed memory and learning problems with age. As predicted, the presence of beta-amyloid in the brains of the rats increased with age. However, unlike previous rodent studies, the rats also developed neurofibrillary tangles.
“This new rat model more closely represents the brain changes that take place in humans with Alzheimer’s, including tau pathology and extensive neuronal cell death,” said Roderick Corriveau, Ph.D., a program director at NIH’s National Institute of Neurological Disorders and Stroke. “The model will help advance our understanding of the various disease pathways involved in Alzheimer’s onset and progression and assist us in testing promising interventions.”
The researchers performed a variety of experiments confirming the presence of neurofibrillary tangles in brain regions most affected by Alzheimer’s such as the hippocampus and the cingulate cortex, which are involved in learning and memory. Further experiments showed that about 30 percent of neurons in these regions died with age, the largest amount of cell death seen in an Alzheimer’s rodent model, and that some glial cells acquired shapes reminiscent of the activated glia found in patients.
“Our results suggest that beta-amyloid can drive Alzheimer’s in a clear and progressive way,” said Dr. Town.
Activation of glia occurred earlier than amyloid plaque formation, which suggests Dr. Town and his colleagues identified an early degenerative event and new treatment target that scientists studying other rodent models may have missed.
The findings support a prime research objective identified during the May 2012, NIH-supported Alzheimer’s Disease Research Summit 2012: Path to Treatment and Prevention, an international gathering of Alzheimer’s researchers and advocates. Improved animal models were cited as key to advancing understanding of this complex disease.
"To fully benefit from this exciting new work, there is a critical need to share the animal model with researchers dedicated to finding ways to delay, prevent or treat Alzheimer’s disease’’ said Neil Buckholtz, Ph.D., of the National Institute on Aging, which leads the NIH effort in Alzheimer’s research. “Accordingly, Dr. Town and his colleagues are working towards making their new rat model easily accessible to the research community.”
Working with a group from Nagasaki University, a research group at the Center for iPS Cell Research and Application (CiRA) has successfully modeled Alzheimer’s disease (AD) using both familial and sporadic patient-derived induced pluripotent stem cells (iPSCs), and revealed stress phenotypes and differential drug responsiveness associated with intracellular amyloid β oligomers in AD neurons and astrocytes.
In a study published online in Cell Stem Cell, Associate Professor Haruhisa Inoue and his team at CiRA and a research group led by Professor Nobuhisa Iwata of Nagasaki University generated cortical neurons and astrocytes from iPSCs derived from two familial AD patients with mutations in amyloid precursor protein (APP), and two sporadic AD patients. The neural cells from one of the familial and one of the sporadic patients showed endoplasmic reticulum (ER)-stress and oxidative-stress phenotypes associated with intracellular Aβ oligomers. The team also found that these stress phenotypes were attenuated with docosahexaenoic acid (DHA) treatment. These findings may help explain the variable clinical results obtained using DHA treatment, and suggest that DHA may in fact be effective only for a subset of patients.
Using both familial and sporadic AD iPSCs, the researchers discovered that pathogenesis differed between individual AD patients. For example, secreted Aβ42 levels were depressed in familial AD with APP E693Δ mutation, elevated in familial AD with APP V717L mutation, but normal in sporadic AD.
"This shows that patient classification by iPSC technology may contribute to a preemptive therapeutic approach toward AD," said Inoue, a principal investigator at CiRA who is also a research director for the CREST research program funded by the Japan Science and Technology Agency. "Further advances in iPSC technology will be required before large-scale analysis of AD patient-specific iPSCs is possible."
The zebrafish revealed a central regulator for the development of the brain histamine system
Research has shown that mutations in the psen1 gene are common in the familial forms of Alzheimer’s disease, and the Presenilin-1 protein that the gene encodes is known to be involved in the cleavage of the amyloid precursor protein. In Alzheimer’s disease the amyloid precursor protein is not cleaved the normal way, and the protein accumulates in the brain damaging neuronal tracts and neurons. It is still unknown if the psen1 gene is involved in the etiology of Alzheimer’s disease via another mechanism.
Professor Pertti Panula’s research team at the University of Helsinki has elucidated the role of psen1 gene in the development of the neuronal histamine system and its modulation. Histamine is one of the neurotransmitters, which all are essential for cognitive functions, which in turn are impaired in Alzheimer’s disease. The histamine system is altered during the progression of Alzheimer’s disease.
In the study the zebrafish was used as a model organism. The rapidly developing zebrafish is suitable as a model organism, as its transparency allows researchers to study the development and function of vital organs. To study the function of psen1 gene, zebrafish that did not produce functional Presenilin-1 protein were generated. Despite the fact that the fish lacked functional Presenilin-1 they were viable and developed until adulthood.
The lack of Presenilin-1 protein induced a change in the behavior of the larval zebrafish, they did not as normal fish react to fast changes in the light intensity. “Based on previous research we know that this change in behavior is associated with lack of histamine in the brain”, Panula explains.
In adulthood the motor behavior of the mutant zebrafish differed from the normal fish: the fish swam by the edges of the arena that was available and avoided the inner part. Previous studies from the group have shown that this behavioral alteration also is due to changes in the histamine system.
The researchers found that larval fish lacking Presenilin-1 protein had significantly fewer histamine neurons; in adulthood the histamine neuron number was significantly increased in these fish when compared with normal fish.
"These results reveal that the psen1 gene is a central regulator of the development of the histamine neurons and that the mutation can cause a persistent lifelong change in the neuronal histamine system. This is a very interesting finding", Panula states.
One interesting remaining question is from where the new histamine neurons arise in the brains of adult zebrafish. Are they newly differentiated stem cells or do other cells become histamine neurons? The answer is not known, but based on these results it is advisable to elucidate the role of Presenilin-1 protein in differentiation of stem cells also in the brains of mammals. “Mammals have stem cells in the hypothalamus, in the same area where the histamine neurons are located in all studied vertebrates”, Panula comments.
Panula empathizes that the published study does not tell about an Alzheimer’s disease mechanism in humans. The new knowledge on the function of psen1 gene and the development of the brain histamine system provided by the study is one step forward to understanding the etiology of the disease.
"We perform basic research on molecular level, from where it is a long way to treatment of human diseases. This type of research provides the findings on which the treatments are finally based", Panula says.
Journal of Neuroscience published the study that was conducted at University of Helsinki Neuroscience center, and Institute of Biomedicine.
(Image: Charles Badland, Florida State University)