# Dysregulation of autophagy-lysosomal function links TBI to late-onset neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $652,128

## Abstract

PROJECT SUMMARY
 Epidemiological data link history of traumatic brain injury (TBI) to increased likelihood of development of
Alzheimer’s Disease (AD) and other AD-related dementias (ADRD) later in life. While recent meta-analyses
estimate the overall risk of dementia attributable to TBI at 5-15%, it remains poorly understood how history of
brain trauma may contribute to neurodegeneration years or even decades later.
 One possibility is that TBI may accelerate detrimental cellular changes occurring during normal brain ageing.
A potential candidate is the autophagy-lysosomal pathway essential for degrading misfolded proteins and
damaged organelles. Autophagy function declines during brain aging and more severely in neurodegenerative
diseases. Thus, accelerated inhibition of autophagy-lysosomal function as compared to that observed in normal
brain aging, could contribute to neurodegeneration observed in AD and other age-related dementias. We recently
demonstrated that autophagy is also inhibited after TBI. This is caused by TBI-induced lysosomal defects and is
associated with profound changes in lysosomal lipid composition. Lysosomal dysfunction associated with
accumulation of lipofuscin and other lipid byproducts in the endo-lysosomal compartments is also observed in
aged mice and is exacerbated by either drug or disease induced demyelinating episodes. Since TBI leads to
myelin damage as well as more general perturbation of lipid metabolism in the brain, lipid-mediated damage
could also lead to lysosomal inhibition after TBI and over time cause accelerated autophagy-lysosomal
dysfunction as compared to that observed during normal aging, thus contributing to AD/ADRD.
 We hypothesize that perturbation of lipid homeostasis after TBI accelerates lysosomal lipid accumulation as
compared to normal aging, leading to lysosomal dysfunction and autophagy defects, thus predisposing to
neurodegeneration and AD/ADRD. In order to test this hypothesis, we will use HILIC-MS/MS based lipidomic
analysis of brain lysosomes, MS-based lipid imaging and complementary IF/IHC and biochemical approaches
to compare changes in lysosomal lipid composition and autophagy-lysosomal function in the brains of normal
aging mice and mice aging after TBI. To test the causative effect of perturbed autophagy and lipid metabolism
on development of AD/ADRD relevant pathological and cognitive phenotypes we will use autophagy hypomorph
Becn1+/- mice and Scarb1+/- mice with hypercholesterolemia. We will also use a fly TBI model to identify additional
autophagy and lipid metabolism genes linking TBI to AD/ADRD. We expect that our data will demonstrate that
perturbation of lysosomal lipid metabolism and autophagy by TBI is an important contributor to subsequent
development of AD/ADRD.

## Key facts

- **NIH application ID:** 10126070
- **Project number:** 5R01NS115876-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** MARTA M LIPINSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $652,128
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126070

## Citation

> US National Institutes of Health, RePORTER application 10126070, Dysregulation of autophagy-lysosomal function links TBI to late-onset neurodegeneration (5R01NS115876-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10126070. Licensed CC0.

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