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Researchers have long known that Alzheimer’s is characterized by abnormal clusters of rogue misfolded proteins. A healthy brain has a “quality control system” that effectively keeps them at bay. But problems start when this system goes wrong. 

These protein deposits, known as plaques and tangles, contribute to neuronal dysfunction and death. “A healthy brain is like a household recycling system,” says Professor Michele Vendruscolo, a co-director of the Centre for Misfolding Diseases and director of the Chemistry of Health building. “If you have an effective system in place then the waste gets disposed of in a timely manner.  If not, over time you accumulate garbage, and all sorts of troubles with it.”

Now Vendruscolo and researchers in the Centre for Misfolding Diseases, working with colleagues at the Taub Institute in New York, Columbia University, The Ohio State University and the University of Rochester, have discovered a gene signature that defines neurons’ ability to maintain an efficient control of tau, the protein that forms the tangles. This discovery could lead to the development of new treatments based on enhancing a neuron’s own ability to eliminate harmful aggregates.

In a paper published in Nature Neuroscience, the scientists explain how they wanted to investigate why aberrant protein aggregates form in some cells but not others.  For example, excitatory neurons, which release neurotransmitters that fire impulses between neurons, seem to be subject to earlier impairment in Alzheimer’s than inhibitory neurons, which inhibit these impulses.

First the researchers confirmed excitatory neurons are more vulnerable than inhibitory neurons to tau accumulation and subsequent cell loss. They suspected that this selective vulnerability was a result of an intrinsic difference in the cellular environment, speculating that the excitatory neurons had a more hospitable ‘tau homeostasis system,” which allowed more tau aggregates to form and persist.

They then demonstrated that the tau homeostasis system in excitatory neurons is more conducive to tau aggregation and susceptible to dysfunction than that of inhibitory neurons.  They also found that glial cells (which surround neurons and provide support for and insulation between them) have higher levels of aggregation protectors than both types of neurons. 

In particular, the researchers identified the gene BCL2-associated athanogene 3 (BAG3) as a central player in the tau homeostasis network.  They found that when they reduced BAG3 levels in primary neurons, pathological tau accumulation increased.  When BAG3 was increased, the level of aggregates fell.  They found that BAG3 is the ‘hub’ gene that governs protein homeostasis, and is responsible for the vulnerability of the neuronal cells to ‘tauopathy’, or damage by tau aggregates.

Vendruscolo says: “Our results indicate that neurons - excitatory neurons in particular - have a cellular environment more vulnerable to pathological tau accumulation compared to glial cells.”  He believes that these findings emphasise the importance of seeking treatments that enhance our natural defense mechanisms.

A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology, Nature Neuroscience 22, 47-56 (2019),  Hongjun Fu, Andrea Possenti, Rosie Freer, Yoshikazu Nakano, Nancy C. Hernandez Villegas, Maoping Tang, Paula V. M. Cauhy, Benjamin A. Lassus, Shuo Chen, Stephanie L. Fowler, Helen Y. Figueroa, Edward D. Huey, Gail V. W. Johnson, Michele Vendruscolo & Karen E. Duff