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2024 Alzheimer's Association Research Fellowship (AARF)

Targeting Polyglutamylated Tubulin as an Early Treatment Strategy for AD

Could modifying the accumulation and movement of abnormal tau in the brain delay or prevent Alzheimer’s disease?

Torben Hausrat, Ph.D.
University Medical Center Hamburg-Eppendorf
Hamburg, Germany


Microtubules are small, tube-like structures that act like a skeleton inside cells, maintaining cell shape. In nerve cells, microtubules also contribute to the formation and maintenance of dendrites (the arm-like branches of nerve cells) and the shape of synapses (specialized connections between nerve cells that enable them to communicate with other nerve cells). In early Alzheimer’s disease, people experience damage to both synapses and dendrites — problems that may contribute to the decline in memory and other cognitive functions.

The protein tau attaches to microtubules, where it helps maintain brain cell structure. Tau may be changed by a process called phosphorylation, or the addition of phosphate molecules to generate phosphorylated tau. In Alzheimer’s, tau becomes excessively phosphorylated (or hyperphosphorylated) and loses its ability to perform its normal functions. Hyperphosphorylated tau also tends to clump together into structures called neurofibrillary tangles. These tangles, which are a hallmark of Alzheimer’s and many other brain diseases, may inhibit cell-to-cell communication in the brain and contribute to brain cell death. Studies also show that before neurodegeneration occurs in individuals with Alzheimer’s, the movement of tau into the dendrites of nerve cells causes the dysfunction and death of synapses. However, the biological mechanisms underlying tau hyperphosphorylation, the movement of tau, and the loss of synapses are unknown. 

Microtubules can be modified by a process called polyglutamylation, or the addition of glutamate molecules. Previous studies suggest that polyglutamylation impacts how microtubules interact with proteins such as tau and may be a prerequisite for tau phosphorylation. Dr. Torben Hausrat and colleagues believe that blocking the process of polyglutamylation on certain parts of microtubules may protect against synaptic loss and cognitive impairment.

Research Plan

The researchers will investigate if modifying the polyglutamylation of specific portions of microtubules shows promise as a potential therapeutic drug target for Alzheimer’s. They will study the brains of genetically modified Alzheimer’s-like mice that also carry a mutation that increases polyglutamylation at specific locations on microtubules. The team will measure the amount of tau and hyperphosphorylated tau in mouse nerve cells and mark where within nerve cells the tau is located. In addition, the team will assess the structure and function of synapses between mouse nerve cells. They will also conduct behavioral tests to assess learning and memory in these mice. 

Next, Dr. Hausrat and colleagues will study whether targeting polyglutamylation at specific locations on microtubules may interfere with microtubule-tau interactions and tau hyperphosphorylation. They will experimentally decrease the amount of polyglutamylation in genetically modified Alzheimer’s-like mice. Following this treatment, the team will conduct behavioral tests of learning and memory and then examine the mouse brains with powerful microscopes.


Results from this study may clarify our understanding of the roles microtubules play in brain disease, as well as the biological mechanisms by which abnormal tau accumulates and moves in the brain in Alzheimer’s and other diseases. If successful, the findings may potentially reveal a new therapeutic target for abnormal tau-related brain diseases.

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