# Project 2 - Astrocytic insulin signaling and AD

> **NIH NIH P01** · UNIVERSITY OF KENTUCKY · 2022 · $621,349

## Abstract

PROJECT 2 – ABSTRACT/SUMMARY
In alignment with the overall proposal and goal of this P01— Strategies for Targeting Astrocyte Reactivity in AD
and ADRD—we believe astrocytes can be targeted to impact a multitude of functions known to be dysregulated
in Alzheimer’s disease (AD) and AD-related dementias (ADRD) because of their close physical proximity to other
cell types and essential role in brain metabolism. It is our intention to use an astrocyte-centric approach to
discover new pathways and signals previously uncharacterized in vivo in order to better address future therapies
targeting the health of astrocytes in AD. Here, we will test the hypothesis that elevating insulin signaling
specifically in astrocytes in mouse models of AD-like pathology, will normalize cerebrovascular, metabolic,
and neuronal Ca2+ network changes commonly associated with AD and ADRD. We will combine our expertise
using intranasal insulin (INI) delivery in combination with two-photon (2P) microscopy in the 5xFAD mouse model
of AD-like pathology to investigate astrocyte-specific overexpression and knockdown of insulin receptors (IR) in
the brain, and will characterize the impact of this manipulation on: (Aim 1) neurovascular unit (NVU) function
using red blood cell flow measures; (Aim 2) astrocytic and neuronal bioenergetics using fluorescent measures
of ATP/ADP ratios, glucose imaging using 2-NBDG, and glucose and lactate levels using multi-electrode arrays
(MEAs); and (Aim 3) neuronal/ astrocytic Ca2+ networks using GCaMP6 fluorescent measures of Ca2+. Results
in 5xFAD males and females will be compared to age-matched WT littermates. All imaging experiments will be
conducted in the somatosensory cortex (S1) at rest and during ambulation in head-fixed mice. We will
corroborate some of our results with hippocampal investigations using electrophysiology in the slice, and also
measure spatial and memory processes using the radial arm water maze (RAWM). Our work will investigate
networks of neurons, astrocytes, and blood vessels as targets of amyloidogenesis and vascular impairment
across sex, and will also test the hypothesis that astrocytes represent a target of INI in the brain and can help
regulate the onset of Ca2+ dysregulation. Together, a conceptually novel and experimentally rich set of data will
be extracted in order to address new potential therapeutic targets in AD and ADRD and to elucidate how
particular elements of the NVU integrate to maintain function in health and disease. Under the leadership of Core
A, our proposed collaborations with the other projects and cores sharing resources and expertise will provide a
unique opportunity to share experimental protocols, data results, and interpretation across groups, and will lead
to a thorough and unprecedented characterization of astrocytic reactivity through the lens of experienced leaders
in the field. This project, within the context of the P01, could lead to a paradigm shift such that astrocyte health
and reac...

## Key facts

- **NIH application ID:** 10495936
- **Project number:** 1P01AG078116-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Olivier Thibault
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $621,349
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495936

## Citation

> US National Institutes of Health, RePORTER application 10495936, Project 2 - Astrocytic insulin signaling and AD (1P01AG078116-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10495936. Licensed CC0.

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