# Cellular senescence, inflammation and neurotransmission in Alzheimer's disease

> **NIH NIH R01** · SOUTHERN ILLINOIS UNIVERSITY SCH OF MED · 2020 · $774,630

## Abstract

Project Summary/Abstract
Alzheimer’s disease (AD) lies on a continuum with dynamic neurobiological and pathological
symptoms / markers, therefore we need to identify novel biomarkers to optimize targeted
therapies for improved patient care. Increasing evidence support that age-related accumulation
of senescent cells, chronic inflammation, and altered glutamate neurotransmission represent
inter-related mechanisms that increase the risk for developing AD. Understanding this interaction
is crucial to identifying novel therapeutic targets for improving patient outcome. Existing data
support the proteinopathy-induced senescent cell hypothesis of AD proposed by Golde and Miller,
whereby soluble and insoluble Aβ activates the innate immune system triggering a self-reinforcing
cycle of pro-inflammatory signaling and cellular senescence, ultimately leading to
neurodegeneration (possibly through altered glutamate neurotransmission), and cognitive decline
in AD. However, the role of Aβ42 and glutamate neurotransmission in this self-reinforcing cycle,
and whether decreasing cellular senescence and / or inflammation can prevent cognitive decline,
is unknown. Addressing this gap in knowledge may be key to identifying underlying mechanisms
and therapeutics that have the ability to alter functional outcomes. To address our central
hypothesis that reducing the burden of senescent cells and shifting the profile of adipokines and
cytokines from pro- to anti-inflammatory will restore glutamate neurotransmission and thereby
slow or prevent AD-related cognitive decline, we will target cellular senescence (Aim 1) or
systemic inflammation (Aim 2) at two distinct time points during disease progression; 1) 4-5
months of age, elevated soluble Aβ42, some plaque buildup, and little to no cognitive decline, and
2) 16-17 months of age, significant plaques accumulation and cognitive decline. This will allow
us to examine both the long term and short term effects of these interventions. The studies will
help determine the mechanisms by which brain aging and Aβ42 impacts the development and
progression of AD and may lead to interventions through identification of novel, disease stage
specific biomarkers and optimal therapeutic treatment windows.

## Key facts

- **NIH application ID:** 9939377
- **Project number:** 5R01AG061937-03
- **Recipient organization:** SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
- **Principal Investigator:** Erin R Hascup
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $774,630
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939377

## Citation

> US National Institutes of Health, RePORTER application 9939377, Cellular senescence, inflammation and neurotransmission in Alzheimer's disease (5R01AG061937-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939377. Licensed CC0.

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