# Cerebral amyloid angiopathy, metabolic dysregulation, and the neurovascular unit - Resubmission - 1

> **NIH NIH RF1** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $3,164,945

## Abstract

The etiology of Alzheimer's disease (AD) is complex and multifactorial. Multiple risk factors through still not well
understood molecular mechanisms are known to influence the individual susceptibility for sporadic AD. One of
the often-overlooked contributors to AD pathophysiology is Aβ accumulation in the cerebrovasculature (CAA),
present in >90% of AD cases. CAA imposes restriction in cerebral blood flow resulting in ischemic white matter
lesions, microhemorrhages, enhanced neuroinflammation, and synaptic dysfunction. Synaptic damage
correlates with loss of cognitive function, is an early event in AD pathogenesis, and worsens with disease
progression. Oligomeric Aβ (oligAβ) has emerged as the species capable to selectively disrupt synaptic
transmission, triggering cascades of events that primarily affect mitochondrial function, disrupting ATP
production, inducing caspase-3 activation, and affecting levels and distribution of synaptic components. Our own
preliminary data in APP Tg lines demonstrate profound changes in pre-/post-synaptic markers, low ATP levels
and reduced mitochondrial activity in isolated synaptosomes. Highlighting the relevance of interlinked metabolic
pathways, we show that hypoxic conditions drastically potentiate the detrimental effects of oligAβ, exacerbating
ROS production and inducing comparable toxicity by 500-fold lower Aβ doses than those required under
normoxia. The affected mechanisms are in part related to the protective redox sensor Nrf2 – downregulated in
AD – as small-molecule Nrf2 activators rescue the in vitro phenotype under normoxic conditions. Notably,
hypoxia triggers activation of the oxygen sensitive HIF-1α pathway via upregulation of Siah2, a hypoxia-inducible
molecule also capable of downregulating Nrf2. We hypothesize that progressive brain hypoperfusion as a result
of CAA precipitate Aβ-induced mitochondrial dysfunction via dysregulation of the Nrf2–HIF-1α oxidative
stress/hypoxia protective response resulting in increased synaptic alterations, neuroinflammation, and vascular
susceptibility to microhemorrhages, events we postulate are amenable for translational interventions. We
propose in vitro studies to identify the protective mechanisms exerted by small molecule Nrf2 activators under
conditions mimicking hypoperfusion, assessing changes in global bioenergetics, functional impact in cell-specific
biological parameters, and regulatory shifts in Nrf2–HIF-1α paths modulated by the hypoxia-sensor Siah2. Data
will be validated in vivo in Tg models with progressive Aβ CAA using 1HMRS, conventional MRI, behavioral
assessments, and LTP measurements, complemented by biochemical dissection of functional components of
the mitochondrial machinery and Nrf2–HIF-1 paths, and their impact on synaptic changes and bioenergetics in
isolated microvessels and synaptic mitochondria. Induction of hyperhomocysteinemia through a diet that results
in cerebrovascular abnormalities, reduced oxygen delivery and cognitive defi...

## Key facts

- **NIH application ID:** 10052197
- **Project number:** 1RF1AG065651-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** JORGE A GHISO
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $3,164,945
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052197

## Citation

> US National Institutes of Health, RePORTER application 10052197, Cerebral amyloid angiopathy, metabolic dysregulation, and the neurovascular unit - Resubmission - 1 (1RF1AG065651-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10052197. Licensed CC0.

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