# Understanding the antagonistic role of proteostasis in Alzheimer  disease and cancer.

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $375,719

## Abstract

Project Summary:
There is an inverse relationship between cancer and neurodegenerative disease. Specifically, people with
Alzheimer’s disease have a lower risk of cancer and vice versa. While there is evidence that immune function
underlies the relationship between non-brain cancer and neurodegenerative disease, we hypothesize that there
is a different cause for this inverse relationship in brain cancers. We believe proteostasis lies at the core of this
relationship for brain cancer. We believe toxic peptides associated with neurodegenerative diseases cause
the cells expressing or containing them to have a decreased ability to produce and maintain functional
proteins. This would mean that these cells with these toxic peptides would have lower effective dosages of
oncogenes.
Alzheimer’s disease (AD) and other dementias are increasingly thought of as diseases of protein misfolding.
Accordingly, much research has found that treatments that increase cells’ abilities to manage misfolded or
aggregated proteins tend to decrease the severity of AD-related phenotypes in model systems.
Overexpression of chaperones tends to suppress AD-related pathologies. Conversely, cancer is a disease
wherein oncogene expressing cells that manage misfolded proteins better, tend to comprise more aggressive
tumors. Therefore, managing misfolded proteins is good for the progression of cancer and bad for the
progression of AD and other neurodegenerative diseases where aggregate management currently seems
to be a critical component of the diseases. Thus, there is an antagonistic role for proteostasis in cancer and AD.
AD and other neurodegenerative disorders cause a significant burden to the proteostatic systems. We believe
that it is this burden that decreases the proteostatic capacities of cells in the brain, and is the cause of the
inverse relationship between AD and various brain cancers, especially glioblastoma, where Ras is a critical
component. We believe this because increased chaperone capacity, which begets increased general
proteostasis causes more severe neoplasia formation in our animal model of Ras-based cancer. Additionally,
higher expression of chaperones decreases the severity of phenotypes caused by toxic peptides (Aβ, Tau and
α-synuclein) in the same animal model system.
In the proposed research, we aim to understand how toxic peptides associated with neurodegenerative
diseases affect Ras-driven neoplasia formation. Conversely, we will determine how phenotypes caused
by these same toxic peptides are changed by nullification or overexpression of chaperones that we have
found to modulate Ras-driven neoplasia formation in our currently funded research designed to understand
what factors cause the incomplete penetrance of neoplasia formation. Thus, in the proposed research we
will take a genetic approach to understand the inverse relationship between brain cancer and
neurodegenerative disease.

## Key facts

- **NIH application ID:** 10118671
- **Project number:** 3R01CA219460-02S1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Alexander Richard Mendenhall
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,719
- **Award type:** 3
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118671

## Citation

> US National Institutes of Health, RePORTER application 10118671, Understanding the antagonistic role of proteostasis in Alzheimer  disease and cancer. (3R01CA219460-02S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10118671. Licensed CC0.

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