# A role for extracellular vesicles in neuroinflammation associated to frontotemporal dementia

> **NIH NIH R21** · THOMAS JEFFERSON UNIVERSITY · 2022 · $429,000

## Abstract

Focal neurodegeneration in the frontotemporal lobes of the human brain accounts for the clinical manifestations
in frontotemporal dementia (FTD), while gliosis account more for the spreading of pathology and the progression
of the disease. Indeed, later stages of FTD are characterized by a substantial, widespread and unresolved
microgliosis that is conceivably a result of the spread of neuroinflammation. Despite strong evidence showing
glial involvement, the mechanisms underpinning the onset and progression of neuroinflammation and the
contribution of glia cells in to the neurodegeneration in FTD are poorly understood.
The most common FTD-causative genetic mutation is an intronic hexanucleotide -(GGGGCC)n- repeat
expansion occurring in the C9orf72 gene. The same intronic expansion is shared by a subset of amyotrophic
lateral sclerosis (ALS) patients, who display motor neuron degeneration related symptoms, which may or may
not appear along with the FTD clinical manifestations. C9orf72, in complex with its protein binding partners,
SMCR8 and WDR41, is known to regulated lysosomes biogenesis, autophagosomes formation and trafficking
of vesicles. In the CNS, the omnidirectional exchange of extracellular vesicles (EVs) is tied to modulation of
microgliosis, astrogliosis and to oligodendrocytes maturation. In in vivo models, EVs derived from pro-
inflammatory activated microglia can spread the inflammatory status. EVs’ contribution to disease progression
has been described in Alzheimer’s disease, ALS, Huntington’s disease, multiple sclerosis, Parkinson’s disease,
prion disease, and traumatic brain injury. Conversely, EVs derived from stem cells can mitigate microgliosis and
revert the neuroinflammation.
In this proposal, we hypothesize that C9orf72 haploinsufficiency, a phenotype reported in C9orf72-linked FTD
and ALS patients, defines a new role for EVs in disease. Brain EVs in a C9orf72 deficient background have the
potential to drive the progression of neuroinflammation. We will test this hypothesis using human cerebral
organoid models cultured from deficient or normal C9orf72 genotypes. We will also assess the therapeutic
potential of stem cell derived EVs in treating the progression of neuroinflammation in these models.

## Key facts

- **NIH application ID:** 10459119
- **Project number:** 1R21NS123845-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Davide Trotti
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2022-05-15 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459119

## Citation

> US National Institutes of Health, RePORTER application 10459119, A role for extracellular vesicles in neuroinflammation associated to frontotemporal dementia (1R21NS123845-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459119. Licensed CC0.

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