# Sepsis and the Systemic Cytokine Storm in Aging and Alzheimer Disease Models

> **NIH NIH RF1** · UNIVERSITY OF FLORIDA · 2022 · $2,218,350

## Abstract

ABSTRACT
Severe infection and sepsis accelerate cognitive decline in older Americans, especially those with incipient
Alzheimer's disease (AD). Sepsis is known to induce a systemic inflammatory `cytokine storm', which wanes with
time. However, this response often persists even after infection resolution in patients. We hypothesize that this
systemic cytokine storm can potentially affect brain neuropathology in both pre-symptomatic AD patients and in
older adults with no known cognitive deficits. In preclinical AD models, both amyloid and tau protein accretion
and pathology are influenced by systemic inflammation. Less is known about the cognitive decline in sepsis
survivors without incipient AD, known as sepsis-associated encephalopathy (SAE), and whether this is related
to development of amyloid and tau neuropathology. Our overarching hypothesis is that sepsis and CCI induce
unique local and systemic immunological responses that directly influence murine AD- and SAE-related
pathology. We hypothesize that in incipient or prodromal AD, sepsis would specifically exacerbate brain health
by exacerbating amyloid and tau neuropathology, while in cognitively normal older individuals, SAE outcomes
would be exacerbated by aging pathways. We will test these hypotheses using 4 specific aims. In Aim 1) we will
evaluate whether age plays a critical role in driving sepsis-induced neurodegeneration and loss of cognition
(SAE) in wild-type mice. Here we propose to employ a survivable cecal ligation and puncture model of
polymicrobial sepsis with daily chronic stress (CLP+DCS) in 6 month (mo) young and 18 mo older adult C57BL/6
(B6) mixed sex mice. Mice will be euthanized at 4 or 8 weeks post-sepsis for inflammatory and neuropathologic
evaluation, which will include analysis of neuronal death, and brain inflammatory changes. Simultaneous spatial
transcriptomic and proteomic profiling (NanoString GeoMx™) will allow assessment of brain region-specific
alterations in response to the peripheral cytokine storm. Plasma will be analyzed for inflammatory cytokines and
selected alarmins. Mice will also undergo cognitive assessment following their septic insult. In Aim 2) we will
evaluate whether CLP+DCS-induced systemic inflammation alters Aβ deposition. Here we will use two APP
transgenic mouse models – the fast progressing TgCRND8 mice and the slow progressing Tg.PrP HuAβ (APPsi)
mice - to assess how systemic cytokine storm modulates amyloid deposition. In Aim 3) we will evaluate whether
systemic inflammation exacerbates tau pathology. We will assess whether sepsis induces tau pathology in AD-
relevant brain areas in the PS19 mice. Finally, in Aim 4) we will test whether prophylactic manipulation of the
immune system alters SAE or AD-associated pathologies in selected animal models. Using an AAV-directed
decoy sIL-10R, we will test whether suppressing IL-10 systemically or in the brain attenuates
neuropathologic/behavioral outcomes. Additional mice will receive metformi...

## Key facts

- **NIH application ID:** 10513525
- **Project number:** 1RF1NS128626-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** PARAMITA CHAKRABARTY
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,218,350
- **Award type:** 1
- **Project period:** 2022-08-15 → 2025-07-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513525

## Citation

> US National Institutes of Health, RePORTER application 10513525, Sepsis and the Systemic Cytokine Storm in Aging and Alzheimer Disease Models (1RF1NS128626-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10513525. Licensed CC0.

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