# Synaptic activity-driven Abeta generation and aggregation

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $736,781

## Abstract

PROJECT SUMMARY/ABSTRACT:
 Numerous biochemical and biophysical studies have demonstrated that amyloid-β (Aβ) aggregates into
toxic oligomers and fibrils when the concentration of the peptide is elevated and the pH is low (Paredes-Rosan
et al. 2019; Zhao et al. 2018). Aβ aggregates can be detected neuron throughout the endo-lysosomal pathway
(Brewer et al. 2020) where pH ranges from 4.5-6.5 which are prime conditions for Aβ to aggregate. However,
what physiological processes influence Aβ aggregation in vivo within this compartment remain unknown.
Elevated synaptic activity increases the formation of Aβ within endosomes before it is secreted into the brain
interstitial fluid (ISF) (Cirrito et al. 2005, 2008). We hypothesize that elevated synaptic activity not only
causes formation of Aβ, but also directly drives formation and release of Aβ aggregates. We propose
that low, physiological synaptic activity causes release of Aβ monomer, whereas high bursts of aberrant
activity reach a threshold when the combination of low pH endosomes with sufficiently high Aβ levels induces
aggregation. We have developed a novel electrochemical micro-immunoelectrode (MIE) technology to
measure Aβ40, Aβ42, or Aβ oligomer levels every 60 seconds in an awake, moving mouse for up to 6 hours in
order to tightly link the amount of synaptic activity with the level and conformation of Aβ. Furthermore, we will
determine if glutamatergic or GABAergic neurons are primarily responsible for producing Aβ and if one type of
neuron is more prone to generate aggregates. All studies will use the APPNLF/NLF knock-in mouse model of
amyloidosis in order to preserve normal expression patterns of APP which is critical for these types of studies.
Our preliminary data demonstrates the tight link between synaptic activity and Aβ generation, as well as the
characterization and specificity of the MIE technology for real-time detection of Aβ levels and aggregates.
Using the MIE, preliminary data suggest that only a slight increase in neuronal activity produces Aβ monomer
but that higher levels of activity induce secretion of Aβ aggregates. Also, our data suggests that excitatory
neurons produce more Aβ than inhibitory neurons. While we propose that synaptic activity is a potent regulator
of Aβ oligomer and fibril formation, we acknowledge that there are several means that will induce and influence
aggregation, such as chaperones like apoE, and that synaptic activity is just mechanism that can generate
these toxic species.
 Aim 1 will determine the threshold of synaptic activity that causes Aβ to aggregate into soluble oligomers
then get released into the brain ISF. Aim 2 will determine whether excitatory or inhibitory neurons release Aβ
monomer or Aβ aggregates, and if that differs between wake and sleep states, since inhibitory tone is much
greater during sleep. Aim 3 will determine if chronically modulating activity of excitatory or inhibitory neurons
within the hippocampus alters development ...

## Key facts

- **NIH application ID:** 10780091
- **Project number:** 1R01AG084717-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** John R Cirrito
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $736,781
- **Award type:** 1
- **Project period:** 2024-04-15 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10780091

## Citation

> US National Institutes of Health, RePORTER application 10780091, Synaptic activity-driven Abeta generation and aggregation (1R01AG084717-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10780091. Licensed CC0.

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