Nature sub-issue: "Someone else" that causes Alzheimer's disease tau neurotoxicity

Researchers from Indiana University School of Medicine have identified a protein that interacts and promotes the spread of the neurotoxic tau, which is mainly found in
neurons that appear abnormal in the brains of Alzheimer's patients.

The study, recently published in Nature Neuroscience, was led by Cristian Lasagna-Reeves, Ph.
D.
, associate professor of anatomy, cell biology, and physiology, and Pablo Martinez, Ph.
D.
, postdoctoral fellow in anatomy, cell biology, and physiology, who is also the paper's first author
.

The team found that a presynaptic scaffold protein, bassoon, contributes to the reproduction and neurotoxicity
of tau seeds.
They studied Bassoon's role
in tau protein through mouse and fruit fly models, as well as human cells and human brain samples.

Lasagna-Reeves said: "The main novelty of this study is that we are the first to discover the tau seed interactome, a tau species that makes up less than 5%
of the total tau protein in the brain.
We are trying to identify proteins
that only interact with tau seeds.
”

Tau seeds are tau species that reproduce in the brain, moving from one neuron to the next, producing neurodegeneration
, Lasagna-Reeves said.
In Alzheimer's patients, the tau protein, which normally helps stabilize microtubules, undergoes misfolding and abnormal shape
.

Previous studies on the effects of tau on neurodegenerative degeneration have identified proteins that interact with most tau proteins
in the brain.
Lasagna-Reeves said that narrowing down their research to tau seeds and the proteins they interact with — an interaction that leads to neurotoxic events in the brain — could lead to more targeted treatments
for Alzheimer's disease.

The researchers found that bassoon exacerbated tau spreading and toxicity
in mouse and fruit fly models.
Bassoon stabilizes tau seeds so that they multiply
in the brain.
Lasagna-Reeves says the protein acts as a scaffold; If bassoon is removed, it will make tau seeds more unstable
.
Martinez said that by lowering bassoon levels in the model, it reduced tau transmission, reduced brain atrophy and improved synaptic and behavioral disorders
of the disease.

Martinez said: "We demonstrated that a small fraction of tau protein in the brain is very toxic to Alzheimer's and other neurodegenerative diseases, and we determined the importance
of these interactors for tau seed protein.
The main message for the future is to target Bassoon and other proteins that interact with tau seeds and translate them into therapeutics
.
”

The lab is working with Indiana University School of Medicine-Purdue Targeted Enablement to Accelerate Alzheimer's Drug Discovery to target bassoon with potential therapies that lower proteins
in the brain.

Bassoon contributes to tau-seed propagation and neurotoxicity