Alzheimer's Disease: Why Some Brain Cells Are More Vulnerable

It is one of the greatest mysteries of medical science: Why do some people get Alzheimer's disease?
By on 07/01/2020 2:00 PM

Source: MedicineNet Health News

It is one of the greatest mysteries of medical science: Why do some people get Alzheimer’s disease?

Answering that question is crucial for the 5.8 million Americans who have Alzheimer’s disease. While genetic studies have shown some people are naturally more vulnerable than others, why the disease starts attacking brain cells remains unknown.

Researchers now believe they have found the reason why some brain cells are more vulnerable to Alzheimer’s disease degeneration, and why some are more resistant. This research about the mysterious fundamental causes of the most common form of dementia may lead to a cure one day. Treatment research for any condition is much more productive when basic science has identified a cellular or molecular disease process to target.

For the first time, scientists have described three of the most plausible contributing causes of Alzheimer’s disease dementia and how they interact at the molecular level in a study published this week in Neuron. They used machine learning, genetically modified mice, and data from more than 30,000 human experiments to explore the relationship between aging, beta-amyloid proteins, and tau proteins.

Howard Crystal, MD, a medical author for MedicineNet, explains what we know about these first two causes in the case of Alzheimer’s disease:

  • Aging: Age is the main risk factor for Alzheimer’s disease. Among people over 65, 15% have the disease. For those over 85, 50% have it. As the US population ages, the need for Alzheimer’s disease treatments is quickly rising.
  • Beta-Amyloid Proteins: The accumulation of this protein in the brain forms the basis for the “amyloid cascade hypothesis.” Since the early 90s, this has been the most widely researched hypothesis as to the cause of Alzheimer’s. About half of people with early-onset Alzheimer’s disease have mutations that cause excess amyloid protein production. But in the vast majority of Alzheimer's disease cases, many scientists believe there is too little removal of this Aβ protein rather than too much production.
  • Tau Proteins: Healthy neurons (brain cells) bind their internal support structure with tau proteins for stability, said Medscape author Shaheen E Lakhan, MD, PhD, MS, MEd. But Alzheimer’s disease causes chemical changes in tau proteins. The tau start to pair with other tau, causing tangles. And when this happens, the neurons’ internal support structure begins to disintegrate.

For years scientists have debated whether amyloid proteins or tau proteins causes Alzheimer’s onset. Scientists know a lot about these causes independently. But understanding their complex interactions is challenging.

For the first time, this study shows an association between tau and amyloid proteins at both the molecular and genetic level. And the authors of this study suggest their approach can help explain why some brain cells are more easily damaged by Alzheimer’s disease.

“What is going on downstream of the amyloid accumulation, and how these plaques trigger neurofibrillary tangles within vulnerable neurons, is much more of a puzzle,” said study author Jean-Pierre Roussarie, senior research associate at the Fisher Center for Alzheimer's Disease Research at Rockefeller University in New York City. “It is a place where we could discover novel therapeutic targets.”

Researchers focused on an area of the brain responsible for memory and our perception of time known as the entorhinal cortex. The researchers attempted to explain why neurons in this brain region seem unusually vulnerable to Alzheimer’s advances. They compared two vulnerable neuron types with five that are resistant to Alzheimer’s disease.

What they found is that these vulnerable brain cells need to regularly remodel their connections to other nearby brain cells, requiring the cells to maintain a high state of plasticity throughout their lives. The researchers suspect that Alzheimer’s disease causes problems in this remodeling process.

This research could only hint at the reasons why. They suspect malfunctioning microtubules lay at the heart of the problem. Microtubules have been described as the architectural struts of nerve cells.

“As key regulators of neuronal architecture and intraneuronal trafficking, microtubules are the endpoint of many neuronal functional processes,” the paper explains.

But what makes the microtubules of some brain cells more vulnerable to Alzheimer’s disease remains unknown. Study authors point to two processes as possible culprits. One is called axonogenesis, which refers to how axons grow along a particular path in the nervous system. The other centers around the release of neurotransmitters from the synaptic vesicle, a part of the brain cell that allows nerve impulses to be shared between cells.

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