Scientists Offer New Alzheimerās, Amyloid Connection Theory
Worldwide, 50 million people are living with Alzheimerās disease and other dementias. According to the Alzheimerās Association, every 65 seconds someone in the United States develops this disease, which causes problems with memory, thinking and behavior.
It has been more than 100 years since Alois Alzheimer, M.D., a German psychiatrist and neuropathologist, first reported the presence of senile plaques in an Alzheimerās disease patient brain. It led to the discovery of amyloid precursor protein that produces deposits or plaques of amyloid fragments in the brain, the suspected culprit of Alzheimerās disease. Since then, amyloid precursor protein has been extensively studied because of its association with Alzheimerās disease. However, amyloid precursor protein distribution within and on neurons and its function in these cells remain unclear.Ā
A team of neuroscientists led by »ĘÉ«Ö±²„ās sought to answer a fundamental question in their quest to combat Alzheimerās disease ā āIs amyloid precursor protein the mastermind behind Alzheimerās disease or is it just an accomplice?ā
Mutations found in amyloid precursor protein have been linked to rare cases of familial Alzheimerās disease. Although scientists have gained a lot knowledge about how this protein turns into amyloid plaques, little is known about its native function in neurons. In the case of more common sporadic Alzheimerās disease, the highest genetic risk factor is a protein that is involved in cholesterol transportation and not this amyloid precursor protein. Moreover, various clinical trials designed to address Alzheimerās disease by minimizing amyloid plaque formation have failed, including one from Biogen announced last month.
In a study published in the journal , , Ph.D., senior author, an investigator at the »ĘÉ«Ö±²„ Brain Institute, and an assistant research professor in »ĘÉ«Ö±²„ās , along with collaborators from , tackle this Alzheimerās disease mystery by devising a multi-functional reporter for amyloid precursor protein and tracking the proteinās localization and mobility using quantitative imaging with unprecedented accuracy.
For the study, Zhang and collaborators genetically disrupted the interaction between cholesterol and amyloid precursor protein. Surprisingly, by disengaging the two, they discovered that this manipulation not only disrupts the trafficking of amyloid precursor protein but also messes up cholesterol distribution at the neuronal surface. Neurons with an altered distribution of cholesterol exhibited swollen synapses and fragmented axons and other early signs of neurodegeneration.
āOur study is intriguing because we noticed a peculiar association between amyloid precursor protein and cholesterol that resides in the cell membrane of synapses, which are points of contact among neurons and the biological basis for learning and memory,ā said Zhang. āAmyloid precursor protein may just be one of the many accomplices partially contributing to cholesterol deficiency. Strangely, the heart and brain seem to meet again in the fight against bad cholesterol.ā Ā
Given the broad involvement of cholesterol in almost all aspects of neuronsā life, Zhang and collaborators have proposed a new theory about the amyloid precursor protein connection in Alzheimerās disease, especially in the surface of those tiny synapses, which triggers neurodegeneration.
āAlthough still in early stages, this cutting-edge research by Dr. Zhang and his collaborators at Vanderbilt University may have implications for the millions of people at risk for or suffering with Alzheimerās disease,ā said , Ph.D., executive director of the »ĘÉ«Ö±²„ Brain Institute and a professor ofĀ biomedical scienceĀ in »ĘÉ«Ö±²„ās Schmidt College of Medicine. āThe number of people in Florida alone who are age 65 and older with Alzheimerās disease is expected to increase 41.2 percent by 2025 to a projected 720,000, highlighting the urgency of finding a medical breakthrough.ā Ā
Locally, Alzheimerās disease affects 11.5 percent of Medicare beneficiaries in Palm Beach County and 12.7 percent of Medicare beneficiaries in Broward County (a nearly 18 percent increase over national average). According to the Alzheimerās Association, Florida is number one in per capita cases of Alzheimerās disease in the U.S.
Study co-authors of āReciprocal Modulation between Amyloid Precursor Protein and Synaptic Membrane Cholesterol Revealed by Live Cell Imaging,ā are Claire E. DelBove and Claire E. Strothman, graduate students; Roman M. Lazarenko, Ph.D., a post-doctoral fellow; Hui Huang, Ph.D.; and Charles R. Sanders, Ph.D., associate dean for research and a professor of biochemistry, all with Vanderbilt University. Ā
This research is funded byĀ the National Institutes of Health (Ģż²¹²Ō»åĢżĀ awarded to Zhang andĀ Ā awarded to Sanders) and the »ĘÉ«Ö±²„ Brain Institute.
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