New Research Reveals The True Primary Cause Of Alzheimer's Disease

New research from investigators at University of California, Riverside suggests that amyloid beta (Aβ) and tau compete with each other for binding sites on microtubules inside neurons, disrupting cellular transport and possibly initiating disease development. The study, published in Proceedings of the National Academy of Sciences, Nexus, focuses on microtubules as a central point of interaction between the proteins and proposes that displacement of tau by Aβ may impair neuronal function before protein aggregation occurs.

The new research runs counter to current thinking that has focused on amyloid beta aggregation as the primary driver of Alzheimer’s disease. Instead, the UC Riverside team found that amyloid beta binds to microtubules with similar affinity to tau, a protein responsible for stabilizing these structures. Using fluorescent labeling, the team tracked amyloid beta interactions and observed that it attaches to microtubules and can displace tau when present at sufficient levels. This displacement may compromise the microtubule network that neurons rely on for intracellular transport.

“Our work shows amyloid beta and tau compete for the same binding sites on microtubules, and that a-beta can prevent tau from functioning correctly,” said first author Ryan Julian, PhD, a professor of chemistry at UC Riverside. Microtubules are a transport pathway within neurons that provide for the movement of essential molecules. Tau’s role in maintaining these structures has been well established, but the interaction between amyloid beta and microtubules has not been researched extensively.

The researchers sought to better understand this relationship after they identified structural similarities between regions of tau that bind microtubules and Aβ peptides. To do this, the investigators labeled Aβ peptides and monitored them for changes in movement and light emission, indicating attachment to microtubules. Additional experiments demonstrated that amyloid beta and tau bind with comparable strength, which gave weight to the team’s hypothesis that Aβ accumulation could displace tau.

“We demonstrate that Aβ also binds to microtubules with affinity comparable to that of tau itself,” the researchers wrote. “We hypothesize that displacement of tau by Aβ leads to microtubule dysfunction and facilitates tau phosphorylation and aggregation.” If this is true, it would recast how protein aggregation impacts AD development indication that is not the initial cause of toxicity.

By showing that Aβ and tau aggregation are downstream effects and not the primary cause of AD, this research has the potential to reconcile many of the inconsistent theories on the development and progression of the disease. The researchers noted their finding also align with evidence that the brain’s ability to recycle proteins slows as a result of aging. Autophagy typically clears proteins like Aβ from cells, but if that ability slows in older people, Aβ may accumulate and begin competing with tau for microtubule binding.

Further, despite genetic evidence linking increased Aβ production to early-onset Alzheimer’s, therapies targeting amyloid aggregation have largely failed. The researchers suggest that focusing solely on plaque removal may overlook earlier intracellular events involving microtubule disruption. For instance, other lines of inquiry have shown that lithium can lower AD risk and that lithium stabilizes microtubules, suggesting that protecting microtubules could counteractive the disruptions caused by Aβ.

According to Julian, this potentially connects the dots of AD findings developed over several decades into a single, concise explanation. “This idea helps make sense of many results that previously seemed unrelated,” Julian said. “It gives us a clearer picture of what may be going wrong inside neurons and where new treatments might start.”

https://www.insideprecisionmedicine.com/topics/translational-research/amyloid-beta-tau-binding-linked-to-microtubule-dysfunction-in-alzheimers-disease/

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New Research Reveals The True Primary Cause Of Alzheimer's Disease