What is it about?
Our research explores the potential mechanical links between two major signs of Alzheimer's disease: intracellular tau tangles and extracellular amyloid plaques. We built a mathematical model to test if the breakdown of anterograde axonal transport of amyloid precursor protein (APP), driven by toxic tau aggregates, causes APP to accumulate in the neuron's soma. This model dynamically couples three processes: the slow axonal transport of tau, tau misfolding and agglomeration, and the fast axonal transport of APP. Because tau clumps together much slower than it moves, we used a quasi-steady-state approximation to formulate and solve our equations. The model indicates that misfolded tau builds up early on in the proximal axon. This buildup reduces the affinity of kinesin-1 molecular motors for their APP cargo, creating an APP accumulation that drastically reduces the amount of APP successfully reaching the synapse.
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Why is it important?
The Alzheimer's research field has heavily focused on the amyloid cascade hypothesis, which has faced recent scrutiny due to failed anti-Aβ therapeutics in Phase III clinical trials. Our work is timely because it provides a mechanistic, mathematical framework supporting the alternative "tau hypothesis," which suggests that tau misfolding begins before Aβ agglomeration and actually drives the subsequent amyloid pathology. Crucially, our findings shift how we view axonal blockages in Alzheimer's disease. We demonstrate that the localized APP traffic jam is merely a symptom of tau toxicity, rather than the primary cause of the transport failure itself. This distinction is vital for pointing future therapeutic interventions toward the correct mechanical targets—specifically the interaction between APP-transporting vesicles and kinesin motors—to potentially stop the disease.
Perspectives
Developing this model was an incredibly rewarding challenge, as bridging the gap between abstract mathematical concepts and tangible biological pathologies is never easy. I have always felt that computational modeling is underutilized in understanding neurodegeneration, and this paper gave me and my co-author the chance to prove its value. We were able to mathematically demonstrate that reducing tau protein can prevent amyloid-β accumulation, a concept that aligns perfectly with recent experimental observations. I hope this work shows that investigating the physical "traffic" mechanics inside our brain cells can be just as exciting as traditional biochemistry. If we can mathematically predict where and how these proteins fail to commute—such as tau aggregating in the proximal axon due to high concentrations of free tau—we might finally figure out how to repair the transport machinery before the damage becomes irreversible.
Andrey V Kuznetsov
North Carolina State University
Read the Original
This page is a summary of: How the formation of amyloid plaques and neurofibrillary tangles may be related: a mathematical modelling study, Proceedings of the Royal Society A Mathematical Physical and Engineering Sciences, February 2018, Royal Society Publishing,
DOI: 10.1098/rspa.2017.0777.
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