# THE ROLE OF ZFYVE21 IN CEREBRAL AMYLOID ANGIOPATHY IN ALZHEIMER'S DISEASE

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $384,362

## Abstract

PROJECT SUMMARY
Cerebral amyloid angiopathy (CAA) is an untreatable vasculopathic condition affecting a vast majority of
patients with Alzheimer's disease (AD). In CAA, fibrils of Aβ(1-40) deposit in cerebral vessels and promote the
development of stenotic lesions, intracranial hemorrhages, and perivascular inflammation. These CAA-
associated vascular pathologies show strong linear correlations with the severity of AD, and are thus believed
to promote neurodegeneration and contribute to AD dementia. How CAA develops is poorly understood and
defining mechanism(s) related to its pathogenesis will define new vascular-based strategies for treating AD.
 Complement (C') are a conserved system of plasma proteins involved in host defense. Upon activation,
C' proteins self-assemble into heterodimeric structures called membrane attack complexes (MAC) that insert
as transmembranous pores into target cell membranes. MAC colocalize with Aβ(1-40) deposits in CAA-
affected vessels showing evidence of EC activation, and inhibition of complement protein C5, which prevents
MAC assembly, blocks progression of AD in a murine mouse model with CAA. In solid organ transplantation,
we identified ZFYVE21 as a novel MAC-induced Rab5 effector that activated non-canonical NF-κB, NLRP3
inflammasomes, and canonical NF-κB to mediate endothelial cell (EC) activation and development of
vasculopathic lesions. As C' activation, EC activation, and similar forms of vasculopathy are observed in CAA,
we explored whether ZFYVE21 signaling may play a role in the development of this condition.
 We thus embarked on studies defining a role for ZFYVE21 signaling in CAA based on the hypothesis
Aβ fibrils activate C' on cerebrovascular ECs to induce ZFYVE21-mediated EC activation to promote CAA
vasculopathy and CAA-related neurodegeneration in AD. AD biopsies showed strong staining for MAC,
ZFYVE21, and its downstream pathways in Aβ-laden microvessels affected by CAA. To develop mechanism(s)
to explain these findings, we optimized an in vitro model of Aβ-induced C' activation that was sufficiently robust
to confirm ZFYVE21-mediated signaling in human cerebrovascular endothelial cells (HBMECs). We developed
new in vitro and in vivo model systems to examine the functional significance of ZFYVE21 signaling with
regards to EC activation, barrier permeability, and macrophage recruitment. In 3 unified aims, we will extend
findings from our original proposal to investigate ZFYVE21-mediated mechanisms of EC activation in CAA. Our
aims will form the basis for a long-term program invested in studying how C' mediates vascular pathologies to
further neurodegeneration in AD.

## Key facts

- **NIH application ID:** 10288327
- **Project number:** 3R01HL141137-04S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Dan Jane-Wit
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,362
- **Award type:** 3
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288327

## Citation

> US National Institutes of Health, RePORTER application 10288327, THE ROLE OF ZFYVE21 IN CEREBRAL AMYLOID ANGIOPATHY IN ALZHEIMER'S DISEASE (3R01HL141137-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10288327. Licensed CC0.

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