# Neuroimmunology of AD and CAA with focus on innate immunity and lymphatics

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2022 · $3,095,865

## Abstract

Project Summary/Abstract
Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) are significant contributors to age-related
dementia and a major economic burden. Current strategies to alleviate AD and CAA pathology and associated
cognitive decline are largely ineffective, necessitating the need for additional therapeutic avenues to be explored,
particularly with a multi-disciplinary team able to achieve a holistic understanding of vascular, neuronal, and
immune events that underlie disease progression. One promising strategy is the augmentation of clearance
pathways – including microglia/macrophage phagocytosis of Ab and meningeal lymphatic drainage of cerebral
spinal fluid (CSF) - that facilitate the removal of toxic, misfolded protein aggregates that represent pathological
hallmarks of AD brains. While the vast majority of prior research has focused on parenchymal Ab pathology and
microglial functions, many patients also display CAA, contributing to vascular dysfunction, and implicating a role
for parenchymal border macrophages (PBMs; perivascular and leptomeningeal, collectively). Thus, we will
explore the complex interactions between the meningeal lymphatic system, CSF flow, PBMs, and parenchymal
microglia in AD and CAA. The overall hypothesis of this PPG is that neuroimmune events, particularly aspects
of the innate immune system and meningeal lymphatics, underlie AD and CAA pathology. We further
hypothesize that devising new therapeutic approaches, harnessing the functions of microglia, PBMs, and the
meningeal lymphatics may represent novel targets to alleviate AD-related cognitive decline. In particular, we will
explore how dysfunction in cholesterol metabolism, apoE, and downstream TREM2 signaling contribute to
homeostatic functions or promote pathological roles of microglia, PBMs, and the meningeal lymphatics,
precipitating Ab pathology. Working as a highly collaborative multidisciplinary team, we will utilize newly
developed innovative tools to explore these hypotheses, including intra-vital imaging approaches, in-vivo
microanalysis, new transgenic mouse lines and unique surgical approaches. The specific projects and cores are
as follows: Project 1: Kipnis, PI: Parenchymal border macrophages in AD and CAA. Project 2: Holtzman, PI:
CAA: Role of ApoE, innate immunity, and meningeal lymphatics. Project 3: Randolph, PI: Interplay between
meningeal lymphatics, high-density lipoproteins and border macrophages in CAA and AD. Project 4: Colonna,
PI: The protein tyrosine kinase Syk drives innate immune responses against AD. Core A: Administration (Kipnis,
PI); Core B: Imaging and surgery core (Randolph, PI).

## Key facts

- **NIH application ID:** 10492254
- **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:** $3,095,865
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492254

## Citation

> US National Institutes of Health, RePORTER application 10492254, Neuroimmunology of AD and CAA with focus on innate immunity and lymphatics (1P01AG078106-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10492254. Licensed CC0.

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