A genetic link to molecular events that precede symptoms of Alzheimer’s disease – sciencedaily

Researchers at Tufts University School of Medicine have discovered a molecular mechanism that causes a “jam” of enzymes traveling up and down neural axons, leading to the build-up of beta-amyloid – a key feature and cause of Alzheimer’s disease. The BACE1 enzyme is saved causing clogging and swelling of axons due to the increased production of the toxic amyloid protein.

The study, published today in Science Translational Medicine, reports that a human mutation more prevalent in African American patients with late-onset Alzheimer’s disease triggers a bottleneck of BACE1 in axons. Identifying this mutation is a key step in understanding the underlying molecular mechanisms of the disease and provides a possible strategy for early diagnosis and targeted treatments.

“In people with Alzheimer’s disease, the onset of symptoms occurs around 20 years after the first changes start to develop in the brain, which makes therapeutic intervention extremely difficult,” said Giuseppina Tesco , professor of neuroscience at Tufts University School of Medicine and senior and correspondent. author of the study. “We therefore wanted to identify the mechanisms leading to axon swelling during the pre-symptomatic phase of Alzheimer’s disease, which in turn could provide a way to detect the disease early and possibly treat it more effectively.”

Tufts researchers previously identified a gene, Gga3, that helps regulate the trafficking of BACE1, or the beta-site APP cleavage enzyme, along the axon. In the new study, researchers found that when the Gga3 gene is mutated or missing in mice, their brains exhibit the same distinctive BACE1 bottleneck in swollen axons that are found in the postmortem brain of patients with early stage Alzheimer’s disease. The researchers found that by disrupting the Gga3 gene, the trafficking of BACE1 and other proteins along the axon is slowed or stopped. They also noted that a mutated or missing Gga3 causes severe accumulation of BACE1 in the axon, resulting in axonal swellings both in cultured neurons and in a mouse model of Alzheimer’s disease prior to deposition. amyloid.

In several clinical trials, BACE inhibitors given to patients with advanced disease who already had significant accumulation of beta-amyloid protein and neuronal damage have failed. The researchers asked if the application of inhibitors in the early stages of the disease might be more effective. They found that the inhibitors prevented axon swelling in mice and even improved the bidirectional flow of BACE1. Their results suggest that earlier application of BACE1 inhibitors may be more effective in slowing the build-up of beta-amyloid protein.

Using data sets from the National Institute of Mental Health of the National Institutes of Health and the Alzheimer’s Disease Neuroimaging Initiative, researchers found that mutations in Gga3 were more common in African Americans diagnosed with Alzheimer’s disease 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 group of patients.

“Our study provides a possible molecular explanation for the prevalence of axonopathy during the early stages of Alzheimer’s disease, before amyloid plaque formation,” Tesco said. “The mutation allowed us to determine that axonal alterations may be caused by the accumulation of BACE1. Now an area of ​​interest could be the inhibition of BACE1 to prevent early axonal damage and perhaps this could as well. slow the development of amyloid plaques leading to disease. “

Researchers note that the presence of neurofilament light chain (NfL) in 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 disease progression. Alzheimer’s at the start of its pre-symptomatic stages.

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Materials provided by Tufts University, Health Sciences Campus. Note: Content can be changed for style and length.

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