A new clinical research by University at Buffalo endocrinologists has shown that a low dose of insulin can suppress the expression in the blood of four precursor proteins involved in the pathogenesis of Alzheimer”s disease.
The research suggests that insulin could have a powerful, new role to play in fighting Alzheimer”s disease.
“Our results show clearly that insulin has the potential to be developed as a therapeutic agent for Alzheimer”s, for which no satisfactory treatment is currently available,” said Paresh Dandona, UB distinguished professor of medicine in the School of Medicine and Biomedical Sciences and senior author on the study.
In the study, 10 obese, type 2 diabetic patients were infused with two 100 ml units of insulin per hour over a period of four hours. The patients were all taking oral drugs to treat their diabetes; none of them were taking insulin or any antioxidant or nonsteroidal anti-inflammatory drugs. The control group received 5 percent dextrose per hour or normal saline solution.
Alzheimer’s disease
The low-dose insulin was found to suppress the expression of amyloid precursor protein, from which beta amyloid is derived. It also suppressed presenilin-1 and presenilin-2, the two subunits of an enzyme that converts amyloid precursor protein into beta amyloid, which forms the amyloid plaques. Insulin also suppressed glycogen synthase kinase, which phosphorylates, or adds on another phosphate group, to another neuronal protein, tau, to form the neurofibrillary tangles, the other important component of Alzheimer”s disease in the brain.
“Our data show, for the first time, that the peripheral mononuclear cells express some of the key proteins involved in the pathogenesis of Alzheimer”s disease,” said Dandona.
“They demonstrate that these cells can be used for investigating the effect of potential Alzheimer”s disease therapies on key proteins involved in the disease.
“Even more importantly, it is likely that insulin has a direct cellular effect on these precursor proteins while also exerting its other anti-inflammatory actions,” he continued.
“If this effect of insulin proves, in larger studies, to be systemic, then insulin may well be a potential therapeutic agent in treating Alzheimer”s disease. The challenge is to deliver insulin directly into the brain, thus avoiding its hypoglycemic effect,” he added.
The study has been published in the Journal of Clinical Endocrinology and Metabolism.
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A well-known chemical process called acetylation has a previously unrecognized association with one of the biological processes associated with Alzheimer’s disease and related disorders, researchers at the University of Pennsylvania School of Medicine have determined.
Tau is one of the primary disease proteins associated with a suite of neurodegenerative diseases. Tau proteins are expressed primarily in the central nervous system where they help with the assembly and stability of microtubules, protein structures that are the backbone of the nerve-cell communication system.
“Acetylation was only detected in diseased brain tissue from patients with Alzheimer’s disease or frontotemporal degeneration, suggesting it may have a role in tau transformation linked to disease onset and progression,” said senior author Virginia M.-Y. Lee, director of Penn’s Center for Neurodegenerative Disease Research.
“This suggests that one type of acetylation is a potential target for drug discovery and biomarker development for Alzheimer’s and related tauopathies.”
The researchers demonstrated that tau acetylation led to a loss of one of its major functions – to promote microtubule assembly, in addition to gaining a toxic function, pathological tau aggregation. Mass spectrometry analysis identified specific acetylation sites in the tau protein sequence that overlapped with known microtubule binding sequences, so acetylation may also play a role in faulty binding of tau to microtubules.
How normal tau becomes disengaged from microtubules to form disease-related clumps remains unknown. This study shows that acetylation is most likely another chemical modification implicated in neurodegenerative disorders to be explored as a potential way to detect and fight brain disease.
The findings have been published in the latest issue of Nature Communications.