# Regulation of Neurodegeneration by Nonpathogenic Cellular Prion Protein and LRP1

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $563,313

## Abstract

Microglial activation and neuro-inflammation regulate disease progression in diverse neurodegenerative di-
seases (NDs), including but not limited to Alzheimer's Disease, Parkinson's Disease, and Tauopathies. Under-
standing pathways that regulate neuro-inflammation in NDs is a significant goal. Cellular Prion Protein (PrPC) is
best known as a GPI-anchored membrane protein that, in rare circumstances, undergoes conformational change
to generate a derivative that aggregates in the brain, causing rapid ND and death. Pathogenic PrPC is trans-
missible. Non-pathogenic PrPC is expressed widely, inside and outside the CNS. Numerous studies in diverse
mouse model systems have shown that PrPC attenuates inflammatory responses, including neuro-inflammation.
We contributed to this field by identifying a system of receptors that mediates the anti-inflammatory activity of
PrPC in macrophages when PrPC is released from cells by ADAM family proteases (S-PrP) or in exosomes and
other extracellular vesicles (EVs). This receptor system includes LDL Receptor-related Protein-1 (LRP1) and
the NMDA Receptor (NMDA-R). Binding of PrPC derivatives to the LRP1/NMDA-R receptor assembly in mac-
rophages blocks pro-inflammatory responses initiated by diverse Pattern Recognition Receptors. We now have
data showing that the PrPC-LRP1/NMDA-R interaction initiates anti-inflammatory cell-signaling in microglia. We
also have shown that the anti-inflammatory activity of S-PrP may be harnessed in small synthetic peptides (14-
mers, 4-mer) corresponding to a putative LRP1-binding motif in PrPC that includes Lys100 and Lys103. The major
goal of this research project is to characterize the activity of PrPC and the LRP1/NMDA-R receptor system in
neuro-inflammation in NDs. A second goal is to test whether PrPC derivatives may be administered therapeu-
tically to amplify the activity of the microglial LRP1/NMDA-R system and thereby attenuate neuro-inflammation.
Three specific aims are proposed. In Specific Aim 1, we will test the ability of anti-inflammatory PrPC derivatives
to regulate microglial activation and secretion of pro-inflammatory mediators by microglia and astrocytes in res-
ponse to proteins that accumulate and aggregate in the extracellular spaces of the CNS in various NDs, including
amyloid-β (Aβ), microtubule-associated protein Tau, and α-synuclein. In Specific Aim 2, the effects of PrPC gene
(Prnp) deletion on biomarkers of microglial activation and neuro-inflammation will be studied in three distinct
mouse models of ND, including AppNL-F mice, P301S-Tau transgenic mice, and mice that receive intracerebral
injections of α-synuclein pre-formed fibrils. In Specific Aim 3, we will replicate the studies proposed in Specific
Aim 2, studying tga20 mice, which express 3-4× more PrPC in the CNS compared with wild-type mice. Next, we
will exploit the known ability of LRP1 to serve as a Blood-Brain Barrier Trojan Horse-receptor that transports
proteins into the CNS and test whethe...

## Key facts

- **NIH application ID:** 11044920
- **Project number:** 1R01NS136112-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** STEVEN L. GONIAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $563,313
- **Award type:** 1
- **Project period:** 2024-09-20 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11044920

## Citation

> US National Institutes of Health, RePORTER application 11044920, Regulation of Neurodegeneration by Nonpathogenic Cellular Prion Protein and LRP1 (1R01NS136112-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11044920. Licensed CC0.

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