Abstract - The Role of Tau in Neurodegeneration

A body of evidence suggests that most neurodegenerative disorders are caused by

proteinaceous aggregates. In Alzheimer's, these aggregates are β‑amyloid plaques and

neurofibrillary tangles of the protein Tau.

Tau has a primary function in the axons to provide structural integrity to microtubules

and the neuron’s cytoskeleton. Tau is regularly post-translationally modified by

phosphorylation, which alters the binding ability of Tau to microtubules and this

regulation, through kinases and phosphatases, is necessary for normal cell functioning.

Tau dysfunction in neurodegenerative disorders occurs primarily due to the

hyperphosphorylation of Tau, which leads to misfolding. Hyperphosphorylation may

occur for a variety of reasons, including mutations which make Tau more prone to

phosphorylation or less prone to dephosphorylation, imbalance and upregulation of tau

kinases or downregulation of tau phosphatases. Additionally, β‑amyloid mediated

toxicity, oxidative stress and neuronal inflammation can also increase Tau misfolding.

In tauopathies (like Alzheimer’s), due to hyperphosphorylation, Tau does not bind to

microtubules, and this leads to an increase in cytosolic Tau concentration, which drives

aggregation and the formation of pretangles – small Tau deposits. Next, PHFs (Paired

Helical Filaments) are formed, which contain beta-pleated sheets. These PHFs then self-

construct and form large tangles called Neurofibrillary Tangles (NFTs).

This leads to both a loss of normal function of Tau, and a toxic gain of function by the

NFTs. As Tau no longer binds to the microtubules, it causes disruption of the

microtubules and the cell cytoskeleton. Additionally, the large NFTs accumulate inside

the neuron, which act as a direct physical barrier which blocks cellular functions and

axonal transport, leading to neurodegeneration.

-Aryaman Deshmukh