# Regional, Synaptic, Cellular Modulation of Abeta Metabolism

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2020 · $1,437,764

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia and a major public health problem. Data
from genetic, biochemical, animal, and human studies suggest that the amyloid-β (Aβ) peptide plays a key
early role in initiating disease pathogenesis and that the microtubule associated protein tau plays a critical role
in neurodegeneration and disease progression. Progressive accumulation of Aβ in the brain appears to
ultimately lead to and exacerbate downstream events directly linked to cognitive decline and dementia such as
inflammation and tau aggregation. Prior to this PPG proposal, we found that synaptic and network activity is
tightly coupled with the release of the Aβ peptide in the extracellular space of the brain as part of a normal
biological process. Our labs discovered some of the cellular mechanisms that link synaptic transmission and
network activity with dynamic changes in Aβ levels in awake, behaving mice with confirmation in human
studies. This collaborative work led to the submission and funding of the current PPG which has been funded
from 4/1/12 to the present. We have made substantial progress over the last 4 years. Some key findings are
that the sleep/wake cycle regulates Aβ levels dynamically with Aβ release being higher during wake and lower
during sleep. This effect, at least in part, is via neuronal activity differences between wake and sleep. We also
found that Aβ and tau release by neurons is controlled by synaptic activity and can be monitored dynamically.
It was also found that Aβ levels, clearance, and aggregation can be strongly influenced by neuronal LRP1 and
heparan sulfate proteoglycans (HSPG). In addition to our findings, increasing evidence indicates that once key
proteins involved in neurodegenerative diseases aggregate in the brain (e.g. Aβ and tau), they appear to
spread from one region to others within neuronal networks that are synaptically connected. There is also
growing evidence that in AD, Aβ aggregation in some way drives the progression and spread of tauopathy. We
believe that new studies are now warranted to understand the relationship between synaptic and network
activity, the sleep/wake cycle, and the impact of the apoE/HSPG/LRP1 on Aβ, tau, and the spreading of these
protein aggregates in the brain. The overall hypothesis of this PPG renewal is that the sleep-wake cycle and
brain network activity modulates both Aβ and tau aggregation and the effect of Aβ on tau spreading. We further
hypothesize that apoE/LRP1/HSPG pathways influence these effects. We will utilize innovative techniques and
approaches to study these hypotheses such as the use of DREADDs, in vivo microdialysis, and
microimmunoelectrodes as well as a variety of genetically modified mouse models and viral vectors. The
specific projects and Cores are listed here. Project 1, D. Holtzman, PI: Effects of the sleep/wake cycle on Aβ,
tau, and spreading. Project 2, J. Cirrito, PI: Neuronal Network Regulation in Aβ...

## Key facts

- **NIH application ID:** 10006903
- **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:** $1,437,764
- **Award type:** 5
- **Project period:** 2012-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006903

## Citation

> US National Institutes of Health, RePORTER application 10006903, Regional, Synaptic, Cellular Modulation of Abeta Metabolism (5P01NS074969-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10006903. Licensed CC0.

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