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Scientists propose a new theory of Alzheimer's amyloid connection

Scientists propose a new theory of Alzheimer's amyloid connection

The background is a picture of neurons (blue). Some of them express the new amyloid precursor protein reporter (green) and the synaptic marker Synaptophysin pHTomato (red). The illustration in the lower left corner illustrates the study-derived etiology model of Alzheimer's disease in which a variety of pathological factors such as aging and abeta converge under presynaptic cholesterol and the cholesterol homeostasis disorder at various pathological endpoints such as synaptic dysfunction and neuronal loss leads . Photo credits: Qi Zhang, Ph.D. and Claire E. DelBove

Worldwide, 50 million people suffer from Alzheimer's and other dementias. According to the Alzheimer's 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 senile plaques in a brain of Alzheimer's patients. This led to the discovery of the amyloid precursor protein, which produces deposits or plaques of amyloid fragments in the brain, the alleged perpetrator of Alzheimer's disease. Since then, the amyloid precursor protein has been extensively studied for its association with Alzheimer's disease. However, the distribution of amyloid precursor proteins within and on the neurons and their function in these cells remains unclear.

A team of neuroscientists led by the Brain Institute of Florida Atlantic University attempted to answer a fundamental question in the fight against Alzheimer's disease: "Is the amyloid precursor protein the mastermind behind Alzheimer's disease or is it just an accomplice?"

Mutations in the amyloid precursor protein have been associated with rare cases of familial Alzheimer's disease. Although scientists have learned a great deal about how this protein turns into amyloid plaques, little is known about its native function in neurons. In the case of more common sporadic Alzheimer's disease, the highest genetic risk factor is a protein involved in cholesterol transport rather than this amyloid precursor protein. In addition, several clinical trials to combat Alzheimer's disease have failed by minimizing the formation of amyloid plaques, including one from Biogen, which was announced last month.

In a study published in the journal Neurobiology of the diseaseQi Zhang, Ph.D., senior author, investigator at the FAU Brain Institute and assistant professor at the FAU's Schmidt College of Medicine, along with staff from Vanderbilt University, counter this Alzheimer's mystery with a multifunctional enigma reporter for amyloid precursor protein and prosecution Localization and mobility of the protein using quantitative imaging with unprecedented accuracy.

For the study, Zhang and his colleagues genetically disrupted the interaction between cholesterol and amyloid precursor protein. Surprisingly, by deactivating the two, they discovered that this manipulation not only interferes with the trade in amyloid precursor protein, but also interferes with the cholesterol distribution at the neuronal surface. Neurons with altered distribution of cholesterol showed swollen synapses and fragmented axons and other early signs of neurodegeneration.

"Our study is intriguing because we've found a special link between amyloid precursor protein and cholesterol, which resides in the cell membrane of synapses, which are points of contact between neurons and the biological basis for learning and memory," Zhang said. "Amyloid precursor protein can only be one of the many accomplices that contribute in part to cholesterol deficiency, and it is ironic that the heart and brain appear to be fighting each other in the fight against bad cholesterol."

With the broad involvement of cholesterol in almost all aspects of neuron life, Zhang and his colleagues have proposed a new theory of the association of amyloid precursor proteins in Alzheimer's disease, particularly in the surface of these small synapses that trigger neurodegeneration.

"Although the cutting edge research of Dr. Zhang and his staff at Vanderbilt University is still at an early stage, it may affect the millions of people with Alzheimer's disease or suffering from it," said Randy D. Blakely, Ph .D. , Executive Director of the FAU Brain Institute and Professor of Biomedical Sciences at the FAU's Schmidt College of Medicine. "The number of people in Florida aged 65 and over who have Alzheimer's is predicted to increase by 41.2 percent to 720,000 by 2025, underscoring the urgency of a medical breakthrough."

Alzheimer's disease affects 11.5 percent of Palm Beach County's Medicare beneficiaries and 12.7 percent of Broward County's Medicare beneficiaries (nearly 18 percent above the national average).

According to the Alzheimer's Association, Florida is number one in the United States in per capita cases of Alzheimer's disease.


Researchers answer decades of questions about proteins found in Alzheimer's brain plaques


More information:
Claire E. DelBove et al. Reciprocal modulation between amyloid precursor protein and cholesterol of the synaptic membrane, demonstrated by live cell imaging Neurobiology of the disease (2019). DOI: 10.1016 / j.nbd.2019.03.009

Provided by
Florida Atlantic University

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Scientists propose new theory of Alzheimer's amyloid connection (2019, April 23)
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