# The Importance of Abnormal Inflammasome Activation as a Risk Factor between Traumatic Brain Injury and Alzheimer’s Disease

> **NIH NIH RF1** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $1,671,321

## Abstract

Traumatic brain injury (TBI) is a risk factor for the development of Alzheimer’s disease (AD) and Alzheimer’s
Disease Related Dementias (AD/ADRD). Although much work has been done in evaluating
pathophysiological mechanisms of TBI and AD, the relationships between these two conditions is not
completely understood. The role of inflammation in the pathophysiology of TBI and neurodegenerative
diseases has been reported in the experimental and clinical literature. Accordingly, TBI and
neurodegenerative diseases share many pathological and immunological hallmarks that indicate potential
relationships that are critical as therapeutic strategies are developed. Recently, our laboratories, as well as
others, have helped clarify the importance of abnormal inflammasome signaling in the pathogenesis of TBI
and in the aging brain. These findings indicate that an innate inflammatory response plays a critical role in
multiple pathophysiological events in neurodegenerative diseases such as AD. New evidence for the
release of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-specks
from microglial cells has provided further evidence for inflammasome activation in AD. Importantly, ASC-
specks with prion-like properties contribute to the deleterious effects of the innate immune response
mediated by the inflammasome. The overall goal of the proposed studies is to determine mechanisms
underlying TBI-induced inflammasome activation as a risk factor for AD and to evaluate targeted
therapeutic approaches to improve outcomes in this patient population. Our central hypothesis is that
inflammasome activation in AD augments TBI-induced inflammation by a mechanism, mediated in part by
extracellular vesicle (EV) containing inflammasome proteins and ASC-speck accumulation, that contributes
to worsened AD pathology and memory impairments. To test this hypothesis the following aims will be
pursued: Aim 1) To determine the temporal profile and the mechanisms underlying the detrimental effects
of TBI on inflammasome activation in AD mice; Aim 2) To investigate the role of abnormal inflammasome
activation and ASC-specks in microglia as an underlying mechanism for the deleterious effects of TBI in
AD mice and Aim 3) To determine the therapeutic effects of inflammasome inhibition and ASC-speck
formation on histopathological and behavioral outcomes after TBI in WT and AD-transgenic mice. The
proposed studies will provide new information on how specific genetic risk factors for AD may heighten TBI-
induced neurodegenerative processes and lead to AD-related pathological and progressive cognitive
decline. Moreover, these studies will advance current inflammasome research into the AD/ADRD field to
elucidate novel mechanisms underlying how TBI contributes to the onset of neurodegenerative disorders, and
provide a new direction for evaluating therapeutic interventions targeting abnormal inflammasome activation
after TBI in AD-transgenic mice for potential...

## Key facts

- **NIH application ID:** 10700483
- **Project number:** 4RF1NS125578-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** JUAN Pablo DE RIVERO VACCARI
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,671,321
- **Award type:** 4N
- **Project period:** 2021-09-20 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10700483

## Citation

> US National Institutes of Health, RePORTER application 10700483, The Importance of Abnormal Inflammasome Activation as a Risk Factor between Traumatic Brain Injury and Alzheimer’s Disease (4RF1NS125578-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10700483. Licensed CC0.

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