# Notch1 and APP signaling in cerebral microvascular dysfunction

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $438,655

## Abstract

Project Summary/Abstract
Cognitive dysfunction and dementia are a major health challenge for the elderly and one of the primary underlying
causes, cerebral small vessel disease (CSVD), contributes to 50% of all dementias worldwide. The breakdown
of blood vascular barrier and impaired lymphatic clearance associated with CSVD are considered early
biomarkers of human cognitive dysfunction, and reduced cortical cerebral blood flow and microvascular leak are
observed during disease onset in both dementia patients and mouse models. One classification of CSVD,
amyloidal CSVD, is characterized by the increased deposition of amyloid beta (Aβ), derived from the pathologic
proteolytic processing of amyloid precursor protein (APP), along and within the brain microvasculature. Amyloidal
CSVD appears in nearly all elderly patients with dementia and in roughly 65-85% of the elderly without dementia.
Reciprocally, impaired blood and lymphatic microvasculature undermine Aβ clearance from the brain
microenvironment, exacerbating Aβ deposition and CSVD pathology. Blood and lymphatic microvascular
dysfunction during amyloidal CSVD are characterized by the disintegration of vascular endothelial cell-cell
adhesions and their primary mediator, vascular endothelial cadherin (VE-cadherin). However, molecular
mechanisms that link Aβ to changes in blood and lymphatic vessel permeability via endothelial cell junctional
instability and VE-cadherin disassembly are unknown. Recently we have identified a novel mechanism by which
the proteolytic processing of the Notch1 receptor is critical for the promotion of microvascular barrier function
through the enhancement of endothelial VE-cadherin junctions. Additionally, our preliminary data suggest that
both Notch1 and APP required association with VE-cadherin junctions for their proper processing by γ-secretase.
Here, building upon mechanistic insights uncovered by two highly complementary laboratories (Kutys and Jun
labs), our research team will apply engineering and experimental approaches that span biological scales from
single molecules to 3D human biomimetic microvessels to investigate our central hypothesis that increased
cerebral Aβ disrupts a critical signaling balance of Notch1 and/or APP processing at VE-cadherin junctions to
drive blood and lymphatic microvascular dysfunction. Together, these studies will define new homeostatic
mechanisms regulating brain blood and lymphatic microvascular function, how these molecular processes may
be disrupted by Aβ, and potentially identify new targets for preventative and therapeutic intervention.

## Key facts

- **NIH application ID:** 10196086
- **Project number:** 1R21AG072232-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Young-wook Jun
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $438,655
- **Award type:** 1
- **Project period:** 2021-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196086

## Citation

> US National Institutes of Health, RePORTER application 10196086, Notch1 and APP signaling in cerebral microvascular dysfunction (1R21AG072232-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10196086. Licensed CC0.

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