# The Role of Immunoproteasome Function in Alzheimer's Disease and Aging

> **NIH NIH RF1** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $2,318,528

## Abstract

ABSTRACT
In Alzheimer's disease (AD), decreased activity of the constitutive form of proteasomes has been reported in the
regions affected by amyloid plaque load and tau accumulation. In contrast to neurons, glial cells, besides
expressing constitutive proteasomes, they express at basal levels specialized type of proteasomes called the
immunoproteasomes that exhibit a higher rate of protein degradation compared to constitutive proteasomes.
Upon inflammatory stimuli, such as pro-inflammatory cytokines IFN-γ or under oxidative stress, the expression
of the immunoproteasome subunits is increased, whereby three catalytic constitutive proteasome subunits (β5,
β1, and β2) are exchanged for immunoproteasome subunits β5i, β1i, and β2i and their proteolytic activities
produce a distinct set of peptides for MHC Class I receptors and T-cell activation.
Because immunoproteasomes are induced during neuroinflammation (the immune response) and oxidative
stress (the non-immune response) in glial cells, their pathophysiological significance in AD is debated. It remains
unclear whether immunoproteasomes, as part of cytokine inflammatory responses, contribute to the etiology of
the AD progression. Or whether the biogenesis of immunoproteasomes that exhibit enhanced activity compared
to constitutive proteasomes is part of a compensatory mechanism in activated glial cells to overcome
inflammatory signals and protein accumulation during oxidative stress.
The goal of the project is to elucidate the functional diversity of immunoproteasome across the tauopathy and
AD knock-in mouse models by generating crosses with double deficient immunoproteasome model (L7M1) -
(Aim 1). Moreover, utilizing single-nucleus RNA-sequencing and mass spectrometry-based quantitative
proteomics, we aim to identify changes at the transcriptome and the proteome levels impacted by deficient
immunoproteasomes in mice - (Aim 2). Elucidating the mechanisms of the neuro-glial feedback loop and the
role of glial cells in the propagation of tau across neurons is the topic of Aim 3. Understanding the true nature of
immunoproteasomes in AD is vital because its proteolytic activity and its biogenesis can be exploited
pharmacologically as a novel therapeutic target against AD.

## Key facts

- **NIH application ID:** 10298389
- **Project number:** 1RF1AG070075-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Natura Myeku
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,318,528
- **Award type:** 1
- **Project period:** 2021-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298389

## Citation

> US National Institutes of Health, RePORTER application 10298389, The Role of Immunoproteasome Function in Alzheimer's Disease and Aging (1RF1AG070075-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10298389. Licensed CC0.

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