# Gut Immunity, Neurovascular Dysregulation and Cognitive Impairment

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $423,750

## Abstract

Alzheimer’s disease and related dementias (ADRDs) are a group of age-related diseases
affecting cognitive function for which no treatments are available. Neuroinflammation and
neurovascular dysfunction have emerged as crucial drivers of disease progression in ADRDs. In
particular, cerebral endothelial cells and microglia, brain resident innate-immune cells, have been
implicated in the accumulation of hyperphosphorylated tau, a microtubule associated protein and
a key feature of ADRD’s pathology. Dysregulation of the peripheral immune system could also
play a role and may influence endothelial and microglial function contributing to cognitive
impairment. However, how the peripheral immune system communicates with the cerebral
microvasculature and microglia to alter cognitive function remains to be fully established.
 IL17-producing T-helper lymphocytes (Th17 cells), a subset of T-helper lymphocytes, and
their signature cytokine, IL17, have been implicated in the mechanisms of cognitive impairment.
Previous data indicate that circulating Th17-derived IL17 acts on cerebral endothelial cells to
induce a deficit in endothelial nitric oxide (NO) promoting tau accumulation and cognitive
impairment. Due to their abundance in the gut, Th17 cells are particularly sensitive to gut bacteria
and alterations in the gut flora are associated with dysregulation of Th17 cells. Segmented
filamentous bacteria (SFB) are commensal bacteria which potently induce gut Th17 cells in mice
and alter the course of models of Th17 cell-associated diseases. Therefore, gut Th17
dysregulation induced by SFB could be used as a model to gain a better mechanistic
understanding of how gut Th17 cells alter brain health. On these bases, we propose to test the
central hypothesis that dysregulation of gut Th17 cells, induced by colonization of the small
intestine with SFB, promotes an IL17-mediated inflammatory response in cerebral endothelial
cells which, in turn, activates microglia, leading to tau accumulation and cognitive impairment. To
this end, the present grant application will examine endothelial function, tau pathology and
cognitive function in a mouse model of SFB colonization to test the following hypotheses in male,
female and aging mice: (1) Gut SFB colonization promotes gut Th17 differentiation, increases
circulating IL17 and induces cerebrovascular and cognitive impairment; (2) Circulating IL17
mediates cerebrovascular dysfunction and cognitive impairment through activation of brain
endothelial IL17 receptors; (3) IL17-induced endothelial pro-inflammatory mediators activate
microglia leading to tau accumulation and cognitive impairment. The proposed studies fill an
obvious gap in the understanding of the effects of gut microbiota on cognition and of the role of
circulating IL17, endothelial cells and microglia in mediating these effects. Furthermore, these
findings may unveil a novel link between microbiota-induced dysregulation of intestinal Th17 cells,
brain tau accumul...

## Key facts

- **NIH application ID:** 10900717
- **Project number:** 5R01NS130045-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Giuseppe Faraco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2022-09-18 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900717

## Citation

> US National Institutes of Health, RePORTER application 10900717, Gut Immunity, Neurovascular Dysregulation and Cognitive Impairment (5R01NS130045-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10900717. Licensed CC0.

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