# Alzheimer's Abeta, Tau, Apolipoproteins and Blood-brain barrier

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $785,580

## Abstract

ABSTRACT
 For the competing renewal of our R01NS34467-19 project, we propose to continue collaborative studies
between the Zlokovic and the Holtzman labs aimed at understanding at the cellular, molecular and systems level,
and in allele-specific and gender-specific manner apolipoprotein E (apoE) effects on the cerebrovascular system,
specifically, 1) how they contribute to Alzheimer’s disease (AD) neurovascular dysfunction, neurodegenerative,
amyloid-β (Aβ) and tau disorders; and 2) how targeting apoE-low density lipoprotein receptor-related protein 1
(LRP1) interactions on different cerebrovascular cell types can mitigate and/or block cerebrovascular and brain
damage causing dementia in AD. We will focus on APOE4, the strongest genetic risk factor for AD, and APOE3
that carries a significantly lower risk for AD. Neurovascular apoE is produced by astrocytes, pericytes, and
vascular smooth muscle cells (VSMCs). Based on published and our pilot data, we hypothesize that apoE
isoform-specific interactions with LRP1 on brain vascular cells provide a pathogenic link to apoE-related
cerebrovascular disorder by controlling in an apoE-isoform-specific manner: 1) cyclophilin A (CypA)-matrix-
metalloproteinase 9 (MMP9) pathway which disrupts blood-brain barrier (BBB) and arterial blood vessels; and
2) Ab and tau clearance on capillary and arterial vessels. Specifically, the apoE4 pathophysiological
cerebrovascular effects accelerate cerebrovascular, neurodegenerative, Ab and tau disorders, whereas apoE3
has less disruptive effects. ApoE allele-specific effects on BBB integrity, vascular and neuronal function and
structure will be studied in new APOE knockinflox/flox E3F and E4F mice with apoE cell-specific deletion from
astrocytes, pericytes, or VSMCs (AIM 1); and, in the context of Ab and tau pathology, in APP/PS1-21 mice (AIM
2) and P301S tau mice (AIM 3), respectively, crossed with our new E3F and E4F mice with apoE cell-specific
deletion from astrocytes, pericytes, or VSMCs. We will therapeutically target LRP1 and CypA-MMP9 pathway
with intravenous cell-specific adeno-associated virus (AAV)-mediated delivery of LRP1 minigene to endothelium
and pericytes, and CypA inhibition with Debio 025. Understanding the effects of astrocyte-derived, pericyte-
derived and/or VSMC-derived apoE on cerebrovascular and neuronal functions, Ab and tau clearance and
pathology, in an allele-specific and gender-specific manner, will advance our understanding of the pathogenesis
and treatment of AD neurovascular dysfunction, neurodegeneration, Ab and tau disorders. If successful, this
could lead to new therapeutic approaches targeting LRP1 and/or CypA-MMP9 pathway in different brain vascular
cells to mitigate and/or block apoE’s cerebrovascular and brain damage causing dementia in AD.

## Key facts

- **NIH application ID:** 10370291
- **Project number:** 5R01NS034467-23
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Berislav V Zlokovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $785,580
- **Award type:** 5
- **Project period:** 1995-09-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370291

## Citation

> US National Institutes of Health, RePORTER application 10370291, Alzheimer's Abeta, Tau, Apolipoproteins and Blood-brain barrier (5R01NS034467-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10370291. Licensed CC0.

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