# Microglial Lysosomal Dysfunction Following Head Trauma Contributes to Tau Pathology in Chronic Traumatic Encephalopathy

> **NIH NIH F31** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $41,108

## Abstract

Abstract: More than 200 million individuals are at risk for chronic traumatic encephalopathy (CTE) each year.
CTE is strongly associated with exposure to repetitive head impacts (RHI) such as those received through
contact sports and military activities. Neuropathologically, CTE is defined by progressive accumulation of
hyperphosphorylated tau (p-tau) which is potentiated by microglial neuroinflammation. RHI exposure can induce
microglial inflammation even before the onset of tau pathology, but the mechanisms connecting RHI,
inflammation, and tau in CTE are unknown, representing a major knowledge gap. Proper lysosomal function in
microglia is a key mechanism of p-tau clearance that, when impaired, contributes to p-tau deposition. Recently,
a genetic risk factor for more severe tau pathology in CTE, TMEM106b, was found to influence microglial
inflammation, tau pathology, and CTE severity. TMEM106b is a lysosome-associated protein and the risk allele
produces larger, poorly acidifying lysosomes, pointing to a potential role for lysosomal processing in CTE
pathogenesis. Furthermore, preliminary single nucleus RNA sequencing (snRNAseq) data from CTE tissue also
suggest an alteration to lysosomal functions in microglia. These data led us to hypothesize that exposure to RHI
triggers persistent microglial lysosomal dysfunction which is exacerbated by TMEM106b genetic risk allele and
drives p-tau deposition in CTE. To address this hypothesis, we will utilize snRNAseq, spatial transcriptomics,
and multiplex immunofluorescence to tease apart the genetic underpinnings of RHI-induced microglial lysosomal
dysfunction and understand its role as a potential mechanism conferring TMEM106b genetic risk for more severe
p-tau pathology in CTE. In Aim 1 we will assess cellularly and spatially resolved genomic changes to microglial
transcripts in individuals with CTE. This will reveal the genomic underpinnings of lysosomal dysfunction following
RHI and allow us to localize these changes to regions of p-tau deposition. In Aim 2 we will examine microglial
lysosomal structure and content, markers of lysosomal function, stress, and protease expression. We will then
analyze the relationship of these changes to TMEM106b allele status, years of RHI exposure, and presence and
severity of CTE pathology. Previous work in the McKee and Cherry Labs (Sponsor and co-sponsor) and
preliminary data have validated the proposed techniques. This work will be the first to study microglial lysosomal
dysfunction as a mechanism of CTE pathology and genetic risk which will significantly advance or understanding
of an early disease process and direct future discovery of novel biomarkers and therapeutically targetable
mechanisms.

## Key facts

- **NIH application ID:** 10852834
- **Project number:** 5F31NS132407-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Morgane LMD Butler
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,108
- **Award type:** 5
- **Project period:** 2023-03-15 → 2024-12-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852834

## Citation

> US National Institutes of Health, RePORTER application 10852834, Microglial Lysosomal Dysfunction Following Head Trauma Contributes to Tau Pathology in Chronic Traumatic Encephalopathy (5F31NS132407-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10852834. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*