Affecting over 50 million people worldwide, Alzheimer’s disease (AD) remains one of the most pressing health crises facing the medical community. Researchers from Saint Michael’s College and the University of Vermont recently collaborated to further our understanding of how Alzheimer’s disease develops in the human brain. The team’s groundbreaking discovery, published in November 2024, hinges on a connection between “waste canals” within the brain and the telltale neurodegeneration associated with Alzheimer’s disease. The research was inspired by an unlikely subject: spider brains. Read on for more information on the team’s findings, which offer a new perspective into the cellular mechanisms driving neurodegeneration.
The Fascinating Link Between Neurodegeneration and Spiders
The researchers initially set out to explore the causal elements of neurodegeneration, which they posited would be associated with “impaired waste clearance” mechanisms within the brains of AD patients. These patients’ brains tend to display aggregated cellular waste in the form of amyloid-β plaques and neurofibrillary tau tangles, both of which are normally cleared in the brains of people without neurodegenerative conditions. The team relied on previous research into spider brains to explore the mechanisms behind this waste buildup. Neuroscientist Ruth Fabian-Fine led the team, building on her previous research into Central American wandering spiders, which suffer from conditions that manifest similarly to degenerative diseases in humans, including AD.
Identifying the Essential “Waste Removal” System
Fabian-Fine’s previous research into Central American wandering spiders revealed a waste-internalizing glial “canal system,” which undergoes structural abnormalities in degenerating spider brains. These structural abnormalities in the glial system are now thought to lead to neurodegeneration, which manifests as the depletion and death of brain cells in spiders. Fabian-Fine’s team wondered if humans exhibit a similar “canal system” that malfunctions in cases of AD and other neurodegenerative diseases. Could that be the key to developing effective treatments against degenerative conditions like AD?
To find out, the team conducted diagnostic neuropathologic examinations of human brains and rodent brains. The scientists eventually gathered strong evidence that neurodegeneration in human and rodent brains may have similar causes to those observed in spider brains; namely, a malfunctioning waste removal system. The scientists uncovered what appears to be a “waste canal system” in the human brain. When functioning properly, this canal system internalizes waste from healthy neurons. However, this system can undergo catastrophic swelling, which leads to neurodegeneration.
“We provide strong evidence that a similar glial-canal system may remove cellular waste from the human and rodent brain,” the team wrote in the research paper. “We postulate that in both spider and human brain degeneration, onset is likely linked to the structural failure of the canal-forming macroglia, which consist of myelin and aquaporin-4 (AQP4)-expressing tanycyte-like cells. We demonstrate that this structural failure results in excessive depletion of neuronal cytoplasm resulting in cell death.” Tanycyte-like cells are glial cells that are similar to tanycytes, which are ependymoglial cells located in the third and fourth ventricles and an important component of the hypothalamic network within the brain.
This link between spider brains and human brains is interesting, but what does it mean for Alzheimer’s disease research? Ultimately, the scientists’ report helps identify underlying causes for neurodegeneration, which may aid future drug development specifically targeting these structural abnormalities. By pinpointing potential causes of waste buildup in the brain, researchers can work to find ways to fight back.
To study Alzheimer’s disease, Scantox offers a variety of preclinical in vitro and in vivo models. In these models, amyloid-β pathology and the waste clearance system can be evaluated by several biochemical and histological approaches, including the A4-assay for the analysis of aggregated Aβ and quantification of aquaporin 4 protein by immunofluorescent labeling. Furthermore, several other typical Alzheimer’s disease-related pathologies, such as neuroinflammation, increased neurofilament light chain levels as an indicator of neurodegeneration, and vascular pathology, can be evaluated.
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