# Parenchymal border macrophages in AD and CAA

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2022 · $628,578

## Abstract

PROJECT SUMMARY
Many diseases of the central nervous system (CNS), including Alzheimer’s disease (AD), are associated with
immune system dysfunction. A population of perivascular and leptomeningeal macrophages (which we
now collectively refer to as parenchymal-border macrophages, or PBMs), resides at the borders of the
CNS parenchyma and interact with the cerebrospinal fluid (CSF). Our preliminary data indicate that
pharmacological or genetic ablation of PBMs leads to impaired vasomotion and disrupted CSF dynamics.
Moreover, our findings show that depletion of PBMs results in buildup of perivascular extracellular matrix
(ECM) proteins and shrinkage of the perivascular space. Aged mice are characterized by impaired CSF
dynamics and this is associated with an altered PBM phenotype (reduced Lyve1 expression and induction of
MHCII). Most surprisingly, injection of macrophage colony-stimulating factor (M-CSF) into the CSF reversed
the age-associated effects on CSF flow, further linking PBM dysfunction to abnormal CSF dynamics. We have
recently showed that the skull bone marrow supplies dural myeloid cells, and that after injury or during
neuroinflammation these cells can invade the CNS parenchyma. Our preliminary results demonstrate that skull
bone marrow-derived monocytes also contribute to PBM turnover. Given the strategic location of the PBMs and
the contribution of skull bone marrow cells to their renewal, in this proposal we will focus on PBMs to
understand their roles in AD. We hypothesize that aging promotes the activation of PBMs and their
acquisition of a pro-inflammatory phenotype, resulting in the build-up of ECM, thus leading to perivascular
spaces less permissive to flow and an overall impairment of CSF dynamics. This in turn contributes to
impaired amyloid clearance from the brain parenchyma and deposition along the vasculature, aggravating
parenchymal amyloidosis and precipitating cerebral amyloid angiopathy (CAA). We further hypothesize that
therapeutic manipulation of the PBMs may improve CSF dynamics and alleviate, at least to some extent, the
pathology associated with AD and CAA. In this project we will closely interact and collaborate with other
projects of the program, as well as the surgery and imaging core. Proof of our hypothesis will introduce a new
player, namely PBMs, in AD and CAA pathophysiology. Not less importantly, it may herald the discovery of
new therapeutic targets and interventions that can delay the onset or even improve the ongoing
pathophysiology of devastating aging-associated neurological diseases.

## Key facts

- **NIH application ID:** 10492257
- **Project number:** 1P01AG078106-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jonathan Kipnis
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $628,578
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492257

## Citation

> US National Institutes of Health, RePORTER application 10492257, Parenchymal border macrophages in AD and CAA (1P01AG078106-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10492257. Licensed CC0.

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