# Neuroinflammatory mechanisms underlying sepsis-induced cognitive dysfunction

> **NIH NIH RF1** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $1,940,638

## Abstract

ABSTRACT
Higher prevalence of sepsis in older individuals is also linked to increased rate of diagnoses for multiple types of
dementia including Alzheimer’s disease and related dementias (ADRD). Chronic impairments include changes
in memory and attention, emotional function and neuromuscular strength which each have a major impact on
patients and families. Exact mechanisms underlying this persistent damage are unknown but data support a role
for chronically activated microglia following infection. Understanding of neurological changes during this critical
time period is hampered by a lack of appropriate animal models and short experimental endpoints. Behavioral
assessments can be severely confounded by hypoactive delirious states and sickness behaviors, and many
studies have been conducted in young rather than aged animals, without additional AD-relevant neuropathology
further limiting interpretive and predictive power. We will address each of these challenges and test the
overarching hypothesis that overarching hypothesis that age and AD neuropathology predispose the brain
to greater neuronal damage, prolonged microglial activation and poorer cognitive outcomes following
sepsis. Further, we hypothesize that microglia of older adults have a more robust inflammatory response
and a reduced ability to downregulate inflammation leading to persistent cognitive impairment,
particularly in the presence of additional AD-relevant neuropathology. Our three aims will be conducted in
young adult (3 months) and aged mice (up to 18 months), and in vivo data will be supported by ex vivo
electrophysiology, immunohistochemistry and molecular biology approaches. We will assess our key outcomes
up to 90 days following recovery from illness. In Aim 1 we will demonstrate the extent of increased risk for
persistent cognitive impairment and prolonged neuroinflammation following sepsis in aged compared
to young animals. We will use a cecal slurry injection to induce sepsis in mice up to 18 months using a rodent
model that recapitulates the major defining features of acute brain dysfunction including: acute
neuroinflammatory response, disrupted EEG patterns, behavioral deficits across a range of cognitive and
neuromuscular domains, and impaired hippocampal long-term potentiation. In Aim 2 we will directly examine
the role of microglia in persistent cognitive impairment following sepsis using clinically relevant
biomarkers, immunohistochemistry morphological quantification of microglia and whole tissue and single cell
RNA approaches. In Aim 3 we will determine the extent to which AD neuropathology contributes to sepsis-
induced cognitive impairment and brain dysfunction. We will compare behavioral outcomes and microglial
response in two different mouse models of AD to test the potential for increased sensitivity to CS in the presence
of common AD neuropathology and gene variants.

## Key facts

- **NIH application ID:** 10525755
- **Project number:** 1RF1AG075341-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Julie A. Bastarache
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,940,638
- **Award type:** 1
- **Project period:** 2022-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525755

## Citation

> US National Institutes of Health, RePORTER application 10525755, Neuroinflammatory mechanisms underlying sepsis-induced cognitive dysfunction (1RF1AG075341-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10525755. Licensed CC0.

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