Researchers at Tufts University School of Medicine discovered a molecular mechanism that causes a “traffic jam” of enzymes traveling up and down neuronal axons, leading to the accumulation of amyloid beta—a key feature and cause of Alzheimer’s disease. The enzyme, BACE1, gets backed up, causing the axons to clog and swell because of the increased production of the toxic amyloid protein.
The study reports that a human mutation more prevalent in African American patients with late-onset Alzheimer’s triggers this traffic jam 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 individuals with Alzheimer’s disease, the onset of symptoms happens about 20 years after the first changes start 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 on the study. “We wanted to identify the mechanisms leading to the swelling of axons during the pre-symptomatic phase of Alzheimer’s disease, which could in turn provide a way to detect the disease early and possibly treat it more effectively.”
Tufts researchers previously identified a gene, Gga3, which helps regulate the traffic of BACE1 along the axon. In a new study, the researchers found that when the Gga3 gene is mutated or missing in mice, their brains present that same distinctive BACE1 traffic jam in swelling axons that are found in the postmortem brains of early stage patients with Alzheimer’s disease.
The researchers found that by disrupting the Gga3 gene, the traffic of BACE1 and other proteins along the axon is slowed or shut down. They also noted that a mutated or missing Gga3 leads to a severe accumulation of BACE1 in the axon, which results in axonal swellings both in cultured neurons and in a mouse model of Alzheimer’s disease prior to amyloid deposition.
Using datasets from the National Institutes of Health’s National Institute of Mental Health and the Alzheimer’s Disease Neuroimaging Initiative, the researchers discovered that mutations in Gga3 were more common among African Americans diagnosed with Alzheimer’s disease than other populations. Although the sample size was small, the researchers believe this finding could positively impact this group of patients, providing a case for identifying early-stage interventions and treatments for the group.