# Effects of the Sleep/Wake Cycle on A-Beta, Tau and Spreading

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2020 · $382,665

## Abstract

PROJECT SUMMARY/ABSTRACT
In most neurodegenerative diseases including Alzheimer's disease (AD), specific proteins that are normally
soluble, aggregate in either the intra- or extracellular space of the brain. In AD, the aggregation of amyloid-β
(Aβ) appears to initiate disease pathogenesis and the aggregation of tau in specific brain regions is associated
with neurodegeneration. Understanding factors that lead to protein aggregation and their spread through
specific neural networks will likely provide important insights for development of new treatments. One factor
that influences the likelihood that Aβ or tau will aggregate is concentration. Prior to and over the first 4 years of
this PPG, project 1, working with the other PPG investigators, has produced strong evidence that something
associated with the sleep wake cycle regulates interstitial fluid (ISF) Aβ levels at least in part via influencing
synaptic activity. Further, manipulations that influence the sleep wake cycle that are linked with increasing or
decreasing ISF Aβ acutely also increase or decrease Aβ deposition chronically if such changes occur over
longer periods of time. While tau is a predominantly a cytosolic protein, we also found that it is present in the
ISF and that its levels there can be regulated by excitatory synaptic activity. A key concept that has emerged in
neurodegenerative diseases is that certain proteins that aggregate, such as Aβ and tau, appear to spread
within the brain. Once aggregation occurs in one region, protein aggregates will often next appear in another
brain region that is in a synaptically connected network. There is strong evidence in AD and in animal models
that Aβ aggregation in some way drives the progression and spread of tauopathy within brain networks. This
spread of protein aggregates may occur via a prion-like mechanism. In prior studies of the sleep/wake cycle,
we performed manipulations that affect more than just sleep (e.g. stress) and did not specifically affect slow
wave sleep. Some important questions remain. Does direct neural manipulation of wakefulness and slow wave
sleep have the same effects we have previously seen in regard to Aβ? Is ISF tau, tau pathology, and tau
spreading acutely and chronically affected by the sleep/wake cycle? How does Aβ influence ISF tau, tau
pathology, and tau spreading in the context of changes in the sleep/wake cycle? We hypothesize that ISF Aβ
and Aβ pathology is strongly affected by the sleep wake cycle and that the ability of Aβ to drive tauopathy
occurs in part via effects of the sleep wake cycle influencing trans synaptic spread of tau aggregates. This
hypothesis will be tested in these aims. Aim 1: To directly manipulate slow wave sleep and wakefulness via
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and determine the acute effects on ISF
Aβ and tau. Aim 2: To determine the effects of modulating the sleep/wake cycle chronically via DREADDs and
other methods on Aβ pathology, ...

## Key facts

- **NIH application ID:** 10006907
- **Project number:** 5P01NS074969-09
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** DAVID M. HOLTZMAN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,665
- **Award type:** 5
- **Project period:** 2012-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006907

## Citation

> US National Institutes of Health, RePORTER application 10006907, Effects of the Sleep/Wake Cycle on A-Beta, Tau and Spreading (5P01NS074969-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10006907. Licensed CC0.

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