# Understanding Roles for Protein Homeostasis Machinery in Aging Brain Vasculature

> **NIH NIH F32** · HARVARD UNIVERSITY · 2022 · $67,582

## Abstract

PROJECT SUMMARY
Aging is the largest risk factor for a majority of neurodegenerative disorders, including Alzheimer’s disease (AD)
and related dementias. Despite growing incidence for such disorders, zero therapeutics are capable of reversing
progression of aging-related cognitive decline seen in disease and healthy aging. Through the use of
heterochronic parabiosis however, or the surgical joining of circulatory systems between young and old mice,
our group demonstrated that blood-borne factors from young animals are capable of reversing many deleterious
phenotypes seen in the aged brain. Understanding the molecular mechanisms underlying cognitive improvement
post-parabiosis may uncover novel therapeutic avenues for aging-related neurodegeneration.
 One hallmark of aging linked to the onset of AD is the collapse of protein homeostasis (proteostasis)
networks that regulate the folding of newly synthesized proteins via molecular chaperones as well as the
degradation of pathologic misfolded proteins. During aging, cellular proteostatic capacity declines, leading to an
increase in protein aggregates with physiological consequences driven by activation of stress response
pathways in downstream cell types. Recently, by profiling transcriptional changes occurring in the aging mouse
brain, our group identified chaperones that decrease in brain endothelial cells (BECs) with age, while
simultaneously, in the same cells, levels of stress-inducible genes known to increase upon sensing misfolded
proteins (e.g. Hspa1a, Hsp90aa1) were elevated – signatures which reversed post-parabiosis. Although BECs
are some of the most vulnerable cells in AD, with many patients exhibiting altered blood-brain barrier (BBB)
integrity, proteostasis machinery of these critical barrier cells has not been investigated.
 Taken together, in aging BECs, (1) molecular chaperones decrease, while (2) stress-inducible heat shock
proteins (HSPs) increase, potentially reflecting the presence of misfolded proteins throughout the aged brain. To
this end, we first seek to identify proteins that aggregate in the brain during aging and upon parabiosis via mass
spectrometry. In doing so, we will profile aging-associated proteins which aggregate in a deleterious, yet
reversible manner. Will then assess the ability of identified aggregation-prone proteins to activate stress
response pathways in BECs. While our first aim asks, what is responsible for activation of stress-inducible HSP
expression in aged BECs, our second asks what impact does increased HSP expression have on BEC function?
This will be assessed by modulating Hspa1a (the most differentially expressed HSP in aging) levels using primary
murine and human BECs alongside AD mutation-containing human induced pluripotent stem cell (iPSC)-derived
BECs via lentiviral constructs. In parallel, we will modulate levels of Hspa1a in vivo specifically within BECs of
mice via adeno-associated viral vectors. Expression of BEC markers and function wil...

## Key facts

- **NIH application ID:** 10537760
- **Project number:** 1F32AG079593-01
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Richard Giadone
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,582
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537760

## Citation

> US National Institutes of Health, RePORTER application 10537760, Understanding Roles for Protein Homeostasis Machinery in Aging Brain Vasculature (1F32AG079593-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10537760. Licensed CC0.

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