# Role of beta-adrenergic receptors in modulation of cognition and central and peripheral immune systems in Alzheimer's disease

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $452,916

## Abstract

Project Summary
The failure of experimental therapeutics for Alzheimer’s disease (AD) in clinical studies emphasizes the need for
novel therapeutic targets with novel mechanisms of action. One strategy is to look to the body’s natural defense
mechanisms. Postmortem studies of AD patients and aged-matched controls have confounded researchers for
years with evidence of known pathological markers of AD in control groups with lack of cognitive impairments.
Rather than asking if elevated beta-amyloid and neurofibrillary tangles are detrimental for neuronal function and
survival, since this has collectively and repeatedly been demonstrated, a more interesting question is, “Why do
many individuals have normal cognition, despite these pathological abnormalities?” The norepinephrine (NE)
system is a key modulator of cognitive function, neuroinflammation and the systemic immune system. Severe
degeneration of NE neurons in AD patients may underlie disease progression at many levels. Adrenergic
receptors on microglia regulate neuroinflammation and govern protective mechanisms for neuronal function and
survival. Migration of peripheral immune cells to the brain is also regulated by NE tone and may be impaired in
AD patients. Using a platform of established learning and memory paradigms, transgenic models of mice
overexpressing human mutant amyloid precursor protein (APP+ mice) or human mutant tau protein (PS19 mice),
and chemogenetic tools to selectively downmodulate the NE system with restoration of tone at specific beta
adrenergic 1 and 2 receptor subtypes (ADRB1 and ADRB2), this proposal will determine the role of noradrenergic
receptor subtypes in AD-like cognitive deficits, neuroinflammation, and pathology. Subsequent experiments will
examine functional consequences of conditional KO of ADRB1 or ADRB2 in myeloid lineage cells (e.g., microglia
and macrophages, but not neurons), first in an acute LPS model of neuroinflammation, and then on pathology,
neuroinflammation and behavior in the 5XFAD mouse model of AD. An in vitro culture platform will examine
molecular mechanisms through which adrenergic agonists modulate inflammation in response to LPS or
oligomeric amyloid beta in isolated primary microglia cultures from transgenic mice with conditional KO of ADRB1
or ADRB2. A final set of studies will determine the role of recruitment of peripheral monocytes to the brain in
prevention of AD-related pathology and cognitive deficits and will determine the contribution of NE tone at ADRB1
and ADRB2 on this recruitment. These final studies will use cutting edge technology for enriching or depleting
peripheral immune cell populations, combined with previously described behavioral platforms, chemogenetic
tools for targeted downmodulation of NE tone, and innovative flow cytometry analysis of brain, blood, spleen and
bone marrow to identify effects of modulation of NE tone on resident microglia, systemic immune cells and
recruitment of systemic immune cells to the br...

## Key facts

- **NIH application ID:** 10174644
- **Project number:** 5R01AG054533-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Mehrdad Shamloo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $452,916
- **Award type:** 5
- **Project period:** 2017-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174644

## Citation

> US National Institutes of Health, RePORTER application 10174644, Role of beta-adrenergic receptors in modulation of cognition and central and peripheral immune systems in Alzheimer's disease (5R01AG054533-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10174644. Licensed CC0.

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