Understanding The “Traffic Jams” Of Neurons In Alzheimer’s Disease

It can take decades for the first symptoms of Alzheimer’s disease to appear — this is why when a loved one starts to show signs of dementia — no one is ever really certain of the precise moment when their mental health took a turn for the worse. However, even before the telltale signs show up in an individual, the brain’s neurons begin to secrete tau proteins, one of the earliest changes we now know occurs as this very devastating neurodegenerative disease runs its course.

Neuroscience has advanced to the degree that high levels of secreted forms of tau — a protein that is typically detected in spinal fluid but can also be found in the bloodstream, is the most reliable way for physicians to determine who is the most at risk of developing Alzheimer’s in their later years. What neurobiologists have yet to understand, however, is why tau proteins are being released by neurons at all as the disease progresses?

“Since tau secretion is one of the earliest events in Alzheimer’s, figuring out why that happens can tell us about the underlying mechanisms of the disease, which is critical for developing therapies. If tau is the smoke, in other words, what is the fire?” says Dr. Scott Small, who is the Boris and Rose Katz Professor of Neurology at Columbia University Vagelos College of Physicians and Surgeons and the director of the Alzheimer’s Disease Research Center at Columbia University. His study was published in the journal Science Translational Medicine.

The Neuron’s Terminal Center “Goes Off Its Rails” With Alzheimer’s

Small’s laboratory recently conducted a new study that suggests the mechanism behind tau secretion in many of his patients — the compounds emanate from small, malfunctioning compartments known as endosomes, within the brain’s neurons, evidence that suggests endosomes consistently play a role in the onset of Alzheimer’s disease.

Think of these endosomes, function as a sort of bus station terminal, signaling the right tracks for proteins to navigate through the brain. Small’s new study found that this traffic of the endosomes was disrupted in around 70% of the patients examined, and that this was even the case with the ones who only displayed initial symptoms of Alzheimer’s.

These results suggest that the first direct evidence that endosomal traffic disruption — something previously identified by Small along with his colleague Dr. Richard Mayeux, the chair of neurology at Columbia, and others as a primary cause of Alzheimer’s disease — is consistently defective among Alzheimer’s patients.

“There was no question that endosomal dysfunction is a component of Alzheimer’s, but just how often it’s involved had been unknown,” says Small’s colleague, Dr. Sabrina Simoes, an assistant professor of neurological sciences at Columbia University Vagelos College of Physicians and Surgeons, who was the research team leader for the study.

Simoes hopes that if pharmaceuticals in the future can target these pathways and somehow restore the flow of endosomes, they could vastly improve the outcomes for a number of Alzheimer’s patients.

The study’s results have promise that go beyond that, making use of new biomarker tools to investigate what other genes could disrupt the process of endosomal trafficking, and what other health issues could play a part in the secretion of tau — such as diabetes or obesity — that could in turn increase the risk of Alzheimer’s

Seeking What They Sought

The team studied mice that suffered from the same endosomal trafficking defect, and isolated three proteins in their spinal fluid that made them unique to healthy rodents: commonly secreted proteins the endosomes carry — both n-APLP1 and n-CHL1. The other kind was tau.

The researchers then turned to analyzing spinal fluid in people. Janssen Pharmaceuticals, who collaborated with the study, designed new biomarkers for both n-APLP1 and n-CHL1. Along with established biomarkers to isolate tau, they recognized a close relationship between the three proteins, indicating tau leaks along the endosomal pathway.

A further analysis in the proteins of Alzheimer’s patients revealed that these three proteins are boosted to abnormal levels in the spinal fluid of roughly 70% of patients, even the ones in its earliest stages who are otherwise functional.

Can Alzheimer’s Be Stopped?

The three newly identified biomarkers from the study could accelerate the rate in Alzheimer’s drug discovery and clinical trials — by tagging patients with malfunctioning endosomes and easily rating the ability of any potential drug when it comes to restoring normal endosomal operations.

Researchers in Small’s lab have also made some progress when it comes to slowing down Alzheimer’s. Just a few years ago, they isolated compounds capable of doing that among neurons in a petri dish, and now they’re in the process of trying to have them produced as therapeutics, while also looking into potential corrective gene therapies that target endosomal trafficking disruption.

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