# Adverse Cerebrovascular Responses to Antibodies Targeting Beta-Amyloid

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $2,342,415

## Abstract

Abstract
Recent positive results in patients passively immunized with anti-Aβ monoclonal antibodies, such as
aducanumab
, lecanemab, and donanemab are encouraging. Unfortunately, the incidence of adverse Amyloid
Imaging Related Abnormalities (ARIA-E and -H) in response Aβ immunotherapy has been alarming. Thus,
there is renewed interest in understanding the cellular and molecular mechanisms that can be targeted to
protect the blood-brain barrier (BBB), during therapeutic interventions that target Aβ. We propose to rigorously
investigate the underlying adverse brain blood vessel responses to passive anti-Aβ immunotherapy that result
in ARIAs, and other potentially adverse cerebrovascular responses. We previously published on a symptomatic
case of ARIA-E that participated in clinical trial with bapineuzumab, and we now propose to use the mouse
version of bapineuzumab, monoclonal 3D6 exclusively for passive anti-Ab immunotherapy in 5xFAD Tg mice.
Aim 1: To investigate the temporal sequence and the vascular aging components that contribute to the
adverse CNS blood vessel responses to passive anti-Ab immunotherapy
First, we will investigate the temporal sequence events including BBB dysfunction, myeloid cell activation
and microhemorrhage formation in response to anti-Aβ immunotherapy in 5xFAD mice. Secondly, we will
probe the role of age on vascular dysfunction and impairment of CSF dynamics in response to immunotherapy.
Aim 2: Investigate the role of human APOE4 versus APOE3 in CNS blood vessel responses to passive
anti-Ab immunotherapy causing ARIA-E and ARIA-H and other adverse cerebrovascular responses
We propose to utilize 5xFAD crossed with
APOE3 KI and APOE4 KI to investigate the increased risk for
individuals with ApoE4 genotype to develop BBB dysfunction and cerebral microhemorrhages (ARIA-H) in
response to anti-Aβ immunotherapy.
Aim 3: Investigating the “cellular mechanisms” underlying the CNS blood vessel responses to passive
anti-Ab immunotherapy that result in ARIA-E and ARIA-H and other adverse vascular events
 We will use two approaches to ablate specific effector cell populations in the CNS. In addition, we utilize a
novel method to enhance perivascular macrophage (PVM) function to clear CAA and strengthen the BBB.
Aim 4: Exploration of the “molecular mechanisms” underlying the brain blood vessel responses to
passive anti-Ab immunotherapy that result in ARIA-E and ARIA-H and other adverse vascular events
We plan to explore 3 molecular mechanisms to intervene in BBB responses to passive anti-Ab
immunotherapy by utilizing: Lipoxin A4 an anti-inflammatory and pro-resolution agent ; a selective gelatinase
MMP-2 and MMP-9 inhibitor SB-3CT that crosses the BBB; and a complement cascade inhibitor PMX205, a
C5aR1 inhibitor that blocks the action of C5a, a highly proinflammatory anaphylatoxin.

## Key facts

- **NIH application ID:** 10855824
- **Project number:** 1RF1NS134046-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** David Hastings Cribbs
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,342,415
- **Award type:** 1
- **Project period:** 2024-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10855824

## Citation

> US National Institutes of Health, RePORTER application 10855824, Adverse Cerebrovascular Responses to Antibodies Targeting Beta-Amyloid (1RF1NS134046-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10855824. Licensed CC0.

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