# Central noradrenergic mechanisms of cerebrovascular pathology in Alzheimer's disease

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2021 · $519,343

## Abstract

Project Summary
The main hypothesis of this proposal is that degeneration of the locus coeruleus (LC) noradrenergic projection
system promotes cognitive impairment in Alzheimer’s disease (AD) by driving forebrain cerebrovascular
dysfunction. We recently demonstrated that LC neuron loss occurs in amnestic mild cognitive impairment
(aMCI) and correlates with poorer cognitive function. Hence, understanding how LC degeneration impairs
cognition may open up new therapeutic avenues. To date, most studies have focused on the role of the LC in
regulating AD neuropathology, yet virtually no attention has been paid to the role of the LC in regulating
cerebrovascular permeability and perfusion in AD. To gauge the scientific premise for pursuing this question,
we administered a dopamine-β-hydroxylase IgG-saporin (DBH-SAP) immunotoxin into the prefrontal cortex
(PFC) of Tg344-19 AD rats, which mimicked LC neuron and fiber loss and resulted in memory impairments.
Strikingly, postmortem analysis revealed evidence of widespread blood-brain barrier leakage and increased
cerebral amyloid angiopathy in DBH-SAP-lesioned AD rats compared to control IgG-saporin (CTL-SAP) rats.
Moreover, pressure myography studies showed blunted vasoreactivity of PFC parenchymal arterioles following
DBH-SAP lesions. To begin to understand the mechanisms for these LC-mediated pathologies, RNA
sequencing was performed on laser-captured PFC vessels from Rush Religious Orders Study (RROS)
subjects. These data revealed a dysregulation of genes mediating vessel permeability and calcium signaling in
aMCI and AD compared to controls. Many of these genes were also dysregulated in vessels harvested from
DBH-SAP-lesioned AD rats, suggesting specific pathomechanic pathways linking LC degeneration with
forebrain vascular dysfunction. Therefore, we designed our Specific Aims to test the extent to which LC
degeneration drives cerebrovascular pathology in target fields (Aim 1) and the potential mechanisms
underlying this phenomenon (Aim 2). In Aim 1, Tg344-19 AD rats will be administered DBH-SAP or CTL-SAP
in the PFC in the presence or absence of the norepinephrine pro-drug L-DOPS or the reuptake inhibitor
atomoxetine. Rats will be assessed for memory function and for cortical perfusion by MRI. Pressure
myography studies will analyze vessel physiology and postmortem analysis will quantify vascular and AD-like
pathology. Spontaneously Hypertensive Stroke Prone rats will also be included to test whether LC cell loss
exacerbates vascular risk factors. In Aim 2, PFC parenchymal vessels from RROS subjects will be analyzed by
RNA-Seq. Target genes that are also dysregulated in PFC vessels from DBH-SAP rats will be validated and
tested for their role in vascular dysfunction using in vitro mechanistic assays. If successful, this proposal will
show that 1) LC degeneration is a nexus lesion that impacts both vascular and neuropathology during the
earliest stages of AD, and that 2) targeting noradrenergic mechan...

## Key facts

- **NIH application ID:** 10086362
- **Project number:** 5R01AG060731-03
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Scott E Counts
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $519,343
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086362

## Citation

> US National Institutes of Health, RePORTER application 10086362, Central noradrenergic mechanisms of cerebrovascular pathology in Alzheimer's disease (5R01AG060731-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10086362. Licensed CC0.

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