# RICTOR dependent microglial polarization in aging

> **NIH NIH R36** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $67,819

## Abstract

Aging is the primary risk factor for most neurodegenerative disorders including Alzheimer's disease (AD). The
dysfunction seen in organisms because of aging has a multifaceted origin at the molecular level.
Understanding how altered molecular signaling in key cellular pathways generates age-related decline is
essential to develop better, more targeted therapies that ameliorate dysfunction. AD and related diseases are
the most crippling cognitive threat to our aging population. There is no cure for AD, and this is partly due to a
poor understanding of how aging and inflammation impact pathogenesis and neural plasticity. It is imperative
that we gain a more comprehensive understanding of the biological basis for brain aging. We hypothesize that
the neuroimmune system plays a critical role in aging pathology. Microglia are the brain's resident macrophage
and the major immune effector in the CNS. “Activated” microglia assume a pro-inflammatory phenotype,
secreting cytotoxic factors. An additional process mediated by anti-inflammatory molecules, inhibits the pro-
inflammatory phenotype and shifts microglial toward a restorative phenotype that promotes debris clearance
and tissue repair. Aging perturbs microglial biology such that aging microglia become hyper-responsive to pro-
inflammatory stimuli, generate excess cytotoxic factors, and become insensitive to anti-inflammatory
molecules. Aged microglia are also increasingly unable to assume an anti-inflammatory phenotype. In this way,
dysfunctional microglia become neurotoxic and increase CNS vulnerability. We have previously described age-
related changes in rodent microglia using mass-spectrometry-based proteomics. We identified RICTOR, a
subunit of mTORC2, as an upstream regulator predicted to be inhibited with age. This prediction coincided with
upregulated pro-inflammatory signaling, downregulated anti-inflammatory signaling, and impaired cellular
metabolism and energy regulation. We validated this finding by demonstrating reduced RICTOR expression in
aged primary mouse microglia when compared with their younger counterparts. We also conducted targeted
knockdown of RICTOR in BV2 cells and observed a phenotype resembling aged microglia, validating a primary
role for RICTOR in the aging phenotype. The present study will determine the consequences of RICTOR
knockdown in vivo on microglial phenotype and cognitive behavior in young mice. We hypothesize that in vivo
microglial RICTOR deletion will induce an aging microglial phenotype that will decrease brain resilience and
have widespread impact on cognition and neural plasticity. We predict that knockout animals will manifest a
phenotype characterized by dysregulated neuroinflammation, impaired cognitive and behavioral performance,
and reduced brain plasticity. Our goal is to identify the molecular substrates of in vivo microglial dysfunction
via mTORC2 signaling with the experiments detailed in the proposal.

## Key facts

- **NIH application ID:** 9914199
- **Project number:** 5R36AG062961-02
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Amadu Jalloh
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,819
- **Award type:** 5
- **Project period:** 2019-04-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914199

## Citation

> US National Institutes of Health, RePORTER application 9914199, RICTOR dependent microglial polarization in aging (5R36AG062961-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9914199. Licensed CC0.

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