# TBI-induced exosome release accelerates Alzheimer's disease pathology

> **NIH VA I01** · VA MEDICAL CENTER - LEXINGTON, KY · 2022 · —

## Abstract

Alzheimer's disease (AD) is characterized by build-up of Aβ peptides forming amyloid plaques and hyper-
phosphorylation of tau protein forming neurofibrillary tangles, a two-fold protein aggregation process leading to
progressive neurodegeneration and cognitive decline. Epidemiological studies show that the risk of developing
AD is 4-fold higher in persons who have experienced head trauma or traumatic brain injury (TBI), which is
prevalent in Veterans returning from active combat. Reasons for this increased risk are unclear and no strategy
to prevent AD pathology exists. A critical barrier to progress is the lack of understanding of how amyloid and
tau are rendered neurotoxic, and how TBI may induce or accelerate this process. Our goal is to understand
and prevent amyloid and tau neurotoxicity and delay the onset and reduce neurodegeneration in AD,
particularly when induced or accelerated by TBI in Veterans. Our central hypothesis is that TBI-induced
shear force shakes and repeatedly bends cilia in astrocytes, which leads to calcium influx, reprogramming of
ceramide metabolism, and sustained secretion of ceramide-enriched exosomes termed “astrosomes”
(immediate effect). Aβ42 and tau associate with ceramide and turn astrosomes into neurotoxic betasomes,
even years after TBI (delayed effect). Betasomes also contain prostate apoptosis response 4 (PAR-4), a
protein sensitizing neurons to ceramide-induced apoptosis. Betasomes are transported to mitochondria, where
they enhance Aβ42 and tau-mediated mitochondrial dysfunction and neurotoxicity. Consistent with our
hypothesis, betasomes are detectable in serum from AD patients and 5xFAD mice and induce mitochondrial
damage, caspase activation, and tau aggregation in N2a cells and primary cultured neurons. Our hypothesis
predicts that astrosome secretion, association with Aβ42 and tau, and neurotoxicity are prevented by blocking
TBI-induced calcium influx and ceramide generation. Our expected outcomes include 1) determining
enzymes in upregulation of ceramide and specific calcium channels that are activated by shear force; 2)
defining a ceramide composition in astrosomes that induces interaction with Aβ42, tau aggregation, and
mito/neurotoxicity; 3) identifying ceramide-modulating drugs and calcium channel blockers that prevent
astrosome secretion, betasome formation, mitochondrial dysfunction, and tau aggregation and neurotoxicity;
and 4) quantifying astrosomes and betasomes in serum that indicate severity of TBI-induced AD (TBI-AD) and
success of therapeutic treatment. The impact of this project on protection of Veterans and public health will
include knowledge needed for the development of new treatment strategies that could delay and/or prevent the
onset of progressive neurodegeneration in AD, in particular when induced by mild TBI in Veterans.

## Key facts

- **NIH application ID:** 10412902
- **Project number:** 5I01BX003643-03
- **Recipient organization:** VA MEDICAL CENTER - LEXINGTON, KY
- **Principal Investigator:** Erhard Bieberich
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412902

## Citation

> US National Institutes of Health, RePORTER application 10412902, TBI-induced exosome release accelerates Alzheimer's disease pathology (5I01BX003643-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10412902. Licensed CC0.

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