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Newswise – BOSTON (Nov 18, 2020, 2:00 pm ET): Researchers at Tufts University School of Medicine have discovered a molecular mechanism that causes a “jam” of enzymes that travel up and down neuronal axons, leading to accumulation of beta amyloid – a key feature and cause of Alzheimer’s disease. The enzyme, BACE1, becomes stronger, causing the axons to obstruct and swell due to increased production of the toxic amyloid protein.
The study, published today in Science Translational Medicine, reports that a more prevalent human mutation in African American patients with late-onset Alzheimer’s triggers a BACE1 engorgement in axons. Identification of this mutation is a fundamental step in understanding the molecular mechanisms underlying the disease and provides a possible strategy for early diagnosis and targeted treatments.
“In individuals with Alzheimer’s disease, the onset of symptoms occurs about 20 years after the first changes begin to develop in the brain, making therapeutic intervention extremely difficult,” said Giuseppina Tesco, professor of neuroscience at Tufts University School. of Medicine and senior and corresponding author of the study. “So, we wanted to identify the mechanisms that lead to axon swelling during the pre-symptomatic phase of Alzheimer’s disease, which could in turn provide a way to detect the disease earlier and possibly treat it more effectively.”
Tufts researchers had previously identified a gene, Gga3, that helps regulate the trafficking of BACE1, or beta-site APP-splitting enzyme 1, along the axon. In the new study, the researchers found that when the Gga3 gene is mutated or missing in mice, their brains exhibit the same characteristic engorgement as BACE1 in swollen axons found in the post-mortem brains of early-stage Alzheimer’s disease patients. . The researchers found that by disrupting the Gga3 gene, trafficking of BACE1 and other proteins along the axon is slowed or stopped. They also noted that a mutated or missing Gga3 leads to severe accumulation of BACE1 in the axon, which results in axonal swelling in both cultured neurons and a mouse model of Alzheimer’s disease prior to amyloid deposition.
In several clinical studies, BACE inhibitors given to patients with advanced disease who already had significant accumulation of beta amyloid protein and neuronal damage were unsuccessful. The researchers asked whether applying the inhibitors in the early stages of the disease might be more effective. They found that the inhibitors prevented axon swelling in the mice and even improved the bidirectional flow of BACE1. Their findings suggest that early application of BACE1 inhibitors may be more effective in slowing the buildup of beta amyloid protein.
Using datasets from the National Institutes of Health from the National Institute of Mental Health and the Alzheimer’s Disease Neuroimaging Initiative, the researchers found that mutations in Gga3 were more common among African Americans diagnosed with Alzheimer’s than other populations. Although the sample size was small, the researchers believe this finding may provide a case for identifying early stage interventions and treatments for this patient group.
“Our study provides a possible molecular explanation for the prevalence of axonopathy during the early stages of Alzheimer’s disease, prior to the formation of amyloid plaques,” Tesco said. “The mutation allowed us to determine that axonal alterations may be caused by the accumulation of BACE1. Now an area of concern could be the inhibition of BACE1 to prevent early axonal damage and perhaps this could also slow the development of amyloid plaques leading to the disease. “
Researchers note that the presence of neurofilament light chains (NfL) in the blood plasma is a marker for axonal damage and could be used to identify the best time to use BACE inhibitors to prevent or slow the progression of Alzheimer’s disease. during its pre-early stage. – symptomatic phases.
The first author of the study is Selene Lomoio of the Tesco Lab at Tufts University School of Medicine. Other authors of the study are from Tufts University School of Medicine, the MassGeneral Institute for Neurodegenerative Disease, and Merck & Co.
This work was supported by awards from the National Institutes of Health’s National Institute on Aging (RF1AG057148), Cure Alzheimer’s Fund, and a BrightFocus Foundation
Alzheimer’s Disease Research Scholarship. The content is the sole responsibility of the authors and does not necessarily represent the official views of the lenders. For disclosure of the conflict of interest, see the study.
Lomoio, S., Willen, R., Kim, W., Ho, KZ, Robinson, EK, Prokopenko, D., Kennedy, ME, Tanzi, RE and Tesco, G. (2020) Gga3 elimination and a rare variant GGA3 associated with late-onset Alzheimer’s disease trigger the accumulation of BACE1 in axonal swelling. Scientific translational medicine. doi: https://doi.org/10.1126/scitranslmed.aba1871
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About Tufts University School of Medicine
Tufts University School of Medicine is an international leader in medical and health education and advanced research. It emphasizes rigorous fundamentals in a dynamic learning environment to educate physicians, scientists and public health professionals to become leaders in their fields. The School of Medicine is renowned for excellence in education in general medicine, biomedical sciences, and public health, as well as research at the cellular, molecular and population levels. It is affiliated with more than 20 university hospitals and health care facilities. Tufts University School of Medicine undertakes research that is consistently ranked among the highest in the nation for its effects on the advancement of medical science and prevention.
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