# Dissect regulation of glial nets surrounding amyloid plaques in Alzheimer's disease

> **NIH NIH RF1** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $1,800,027

## Abstract

PROJECT SUMMARY
The pathophysiology of Alzheimer’s disease (AD) remains unclear. Amyloid plaques are surrounded by reactive
astrocytes and microglia, forming glial nets that affect amyloid spreading and inflammatory milieu. However, the
mechanisms of inter-glial communication in glial nets are poorly understood. Our recent integrated network
analysis of -omics data from late-onset AD patients identified the axon guidance receptor Plexin-B1 as a hub
gene in an astrocyte-specific subnetwork. We have confirmed that Plexin-B1 is predominantly expressed in
astrocytes and that it is upregulated in glial nets of AD patients. Remarkably, our pilot study with an
amyloidogenic mouse model of AD showed that Plexin-B1 deletion markedly altered the structure of peri-plaque
glial nets. Plexin-B1 deletion resulted in attenuated astrocyte reactivity, reduced cellular spacing of glial nets,
and a higher coverage of plaques by microglia, leading to a shift of plaques to a dense core type. These changes
of glial nets were associated with an overall reduction in plaque burden and neuritic dystrophy. Here we will
expand our preliminary studies to further test the central hypothesis that glial activation and cellular interactions
in glial nets, as regulated by Plexin-B1, affect amyloid aggregates and neurotoxicity in AD. Blocking Plexin-B1
may thus present a new opportunity to attenuate astrocyte reactivity in glial nets, reducing amyloid burden and
neuroinflammation, thereby slowing down AD progression. In Aim 1, we aim to build cell type-specific glial
signaling networks in AD, and to identify Plexin-B1-mediated gene modules in glial nets. We will analyze single
cell transcriptomic data from both AD patients and AD mice (with and without Plexin-B1 deletion) to define
coregulated gene networks in reactive astrocytes and activated microglia that are associated with Plexin-B1
signaling. In Aim 2, we will carry out a series of functional assays in glial cultures to study the role of Plexin-B1
in mediating astrocyte activation upon amyloid challenge. Human iPSC-derived astrocytes with Plexin-B1
deletion by CRISPR-Cas will be compared to primary astrocytes from Plexin-B1 mutant mice. We will then model
in astrocyte/microglia co-cultures glial interactions in response to amyloid challenge in dependence of Plexin-
B1. In Aim 3, we will conduct in vivo studies using mouse AD models to investigate in detail the impact of Plexin-
B1 deletion on glial nets, plaque deposition, neuronal function and cognitive performance. Both an amyloidogenic
and a tauopathy model of AD will be evaluated at early and advanced stages. We expect to demonstrate that
Plexin-B1 deletion leads to attenuated astrocyte reactivity in glial nets, reduced cellular spacing, increased
microglial coverage of amyloid plaques, and a shift to dense-core plaques and thus less neurotoxicity, as
indicated by pilot data. Altogether, our study will provide new insights into the contribution of glial nets and Plexin-
...

## Key facts

- **NIH application ID:** 10467139
- **Project number:** 1RF1AG077828-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Roland Horst Friedel
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,800,027
- **Award type:** 1
- **Project period:** 2022-05-05 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467139

## Citation

> US National Institutes of Health, RePORTER application 10467139, Dissect regulation of glial nets surrounding amyloid plaques in Alzheimer's disease (1RF1AG077828-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10467139. Licensed CC0.

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