# Contribution of peripheral immune dysregulation to Alzheimer's disease

> **NIH NIH R03** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $338,416

## Abstract

PROJECT SUMMARY
 Alzheimer's disease (AD) is characterized by complex relationships between multiple interrelated
biological and pathologic processing. Research efforts have largely focused on aberrantly aggregated
oligomeric beta-amyloid (oAβ), hyperphosphorylated tau proteins in the brain and more recently, glia-mediated
neuroinflammation. Increasing evidence suggests that the peripheral immune system may play a role in the
pathogenesis of AD. This is supported by the detection of CD8+ T cells adjacent to plaques inside the brain, as
well as a negative association between the number of CD8+ T effector memory cells in the blood of AD
subjects and their cognitive function. Moreover, human plasma proteomic assessments have identified the
alteration of multiple immunological pathways in AD subjects. The brain is protected by the blood brain barrier
(BBB) and communicates with the outside through the choroid plexus, meningeal linings and perivascular
spaces. In AD and other neurodegenerative conditions, the BBB integrity is compromised, which may further
facilitate the migration of peripheral cells and exchange of immune mediators to the affected brain region.
 The quality and the quantity of immune responses in the periphery are primarily determined by aging.
Both adaptive and innate immunity in the periphery are known to precipitously decline during aging. Peripheral
immune dysregulation is also influenced by environment and lifestyle factors, such as psychological stress and
metabolic disorders. Both chronic stress and metabolic disorders are known risk factors for AD. In this pilot
application, we will investigate the role of peripheral immune dysregulation in the onset and progression of AD
in an Aβ mouse model and to identify the immune components that are involved in the process. Specifically,
we will transplant bone marrow from 1) young control mice, 2) old mice, 3) psychologically stressed mice and
4) mice with increased basal inflammation to the young AD mice and we will use neurobehavioral,
immunohistological and molecular biology tools to examine AD-associated neuropathology and cognitive
function and to assess immunological changes in the periphery, the brain and the BBB.
 Our study will provide a proof-of-concept as to whether dysregulated peripheral immune system may
contribute to the onset and progression of AD-type neuropathology and cognitive dysfunction. Our study will
pinpoint the anatomical location and the identities of the peripheral immune components that are involved in
the process for future in depth investigations. A successful outcome of the study will also provide impetus to
investigate the role of peripheral immunity in other models of neurodegeneration.

## Key facts

- **NIH application ID:** 10110822
- **Project number:** 1R03AG070506-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jun Wang
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $338,416
- **Award type:** 1
- **Project period:** 2021-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10110822

## Citation

> US National Institutes of Health, RePORTER application 10110822, Contribution of peripheral immune dysregulation to Alzheimer's disease (1R03AG070506-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10110822. Licensed CC0.

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