# Cellular and Molecular Basis of Sleep Loss Neural Injury in Alzheimer Disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $755,571

## Abstract

ABSTRACT
Chronic short sleep (CSS) is common in developed countries and yet is likely to be a key modifier of
Alzheimer disease (AD), the most prevalent tauopathy in older adults. Sleep loss acutely increases tau
in humans and in mice, and we have recently shown that CSS hastens the temporal progression of
tauopathy in the P301S murine model of tauopathy, increasing all aspects of tauopathy, including soluble
tau oligomers, pathologic tau aggregation, gliosis, neuron loss and neurobehavioral impairment. The fact
that all aspects of tauopathy are impacted by sleep loss leads us to hypothesize that CSS targets a key
upstream initiating factor. Hippocampal calcium/calmodulin dependent kinase II (HC CAMKII) neurons
are among some of the most vulnerable neurons in AD and show early tau accumulation. We find that
CSS massively increases calcium transients in HC CAMKII neurons, activates CAMKII and calpain, and
induces uncompensated endoplasmic reticulum stress with loss of molecular chaperone BiP. Our overall
hypothesis is that CSS results in excessive intracellular calcium bursts in HC CAMKII neurons, leading
to sustained CAMKII and calpain activation, pathogenic tau modifications, and chronic uncompensated
endoplasmic reticulum stress with loss of BiP that feeds back positively to perpetuate injury. Here we
propose to critically test the role of each component of our working model in the biochemical, pathological
and behavioral aspects of tauopathy and CSS-hastening of tauopathy in the P301S model. In Aim 1, we
will test the role of CSS-increased calcium and calpain in HC CAMKII neurons in the CSS HC tau changes
by genetically suppressing local HC CAMKII calcium and calpain, while verifying suppressed calcium
transients with in vivo calcium imaging of CAMKII neurons. In Aim 2, using pharmacologic inhibition and
conditional HC transgenic knock down of CAMKII across CSS, we will determine to what role CAMKII
induces CSS-induced HC ER stress and CSS effects on tauopathy, and in Aim 3, we will critically test
the role of CSS-reduced BiP in the temporal progression of tauopathy and CSS effects on tauopathy.
Collectively, the proposed studies will identify important in vivo mechanisms by which CSS hastens the
temporal progression of tauopathy and will substantiate therapeutic avenues to lessen CSS exacerbation
of tauopathy and tauopathy progression in general.

## Key facts

- **NIH application ID:** 10143167
- **Project number:** 5R01AG064231-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** NIRMALA NIRINJINI NAIDOO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $755,571
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143167

## Citation

> US National Institutes of Health, RePORTER application 10143167, Cellular and Molecular Basis of Sleep Loss Neural Injury in Alzheimer Disease (5R01AG064231-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10143167. Licensed CC0.

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