# LRP4 deficiency in Alzheimer's disease development

> **NIH NIH RF1** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $2,846,666

## Abstract

Alzheimer's disease (AD), the most common form of dementia, affects 10% of the population
aged 65 and older, and up to 50% of people over 85 years old1,2. Patients with AD suffer from a
decline in episodic memory with inability to recall the recent past and eventual loss of long-term
memories, loss of cognitive function and changes in personality. The major goal of this proposal
is to define pathways for the clearance of amyloid-β (Aβ), whose aggregation into amyloid
plaques is a hallmark of AD. Increasing evidence indicates an important role of astrocytes, the
most abundant cell type among glial cells in the brain, in Aβ clearance. This proposal will focus
on a potentially novel regulatory mechanism for astrocytic Aβ uptake by LRP4 (LDLR-related
protein 4), an LDLR-like protein that is abundantly and specifically expressed in astrocytes. We
and others have demonstrated that LRP4 is critical to the formation of the neuromuscular
junction (NMJ) where it serves as a receptor for agrin, a factor from motoneurons. The agrin-
LRP4 interaction activates the transmembrane tyrosine kinase MuSK to induce AChR clustering
and NMJ formation. Results of our preliminary studies, some of which were published, suggest
that LRP4 may play a role in regulating AD pathogenesis. First, LRP4 was selectively expressed
in astrocytes in the hippocampus and prefrontal cortex (PFC), both AD-vulnerable regions. Its
level in astrocytes was higher than those of LDLR and LRP1, both of which have been
implicated in Aβ uptake. Second, LRP4 was reduced in postmortem brain tissues of AD patients.
In accord, deleting LRP4 augmented Aβ plaques and AD-associated deficits in 5xFAD mice, an
AD mouse model. Third, Aβ uptake was impaired in LRP4 mutant (mt) astrocytes. These results
suggest a critical role of LRP4 to astrocytic Aβ uptake. What is the underlying mechanism(s) by
which LRP4 regulates Aβ uptake? LRP4 is a single transmembrane protein with a large
extracellular domain (ECD). Interestingly, we found, in addition to agrin, LRP4 can interact with
ApoE, whose ε4 allele (ApoE4) impairs Aβ clearance. Further pilot studies indicate, first that
agrin stimulation could increase Aβ uptake by astrocytes, in a manner dependent on LRP4. LRP4
could interact with agrin, which has been shown to associate with Aβ. Therefore, we posit that
LRP4 serves as a receptor for ApoE- and agrin-mediated Aβ uptake. Second, LRP4 could
interact with the prorenin receptor (PRR), an auxiliary protein of v-ATPase that is critical to
maintaining endolysosomal pH, and is required for its down-regulation. LRP4 deficiency
increased PRR levels and caused hyper-acidification of endolysosomes. Therefore, we postulate
that PRR upregulation may be a mechanism of LRP4 deficiency. Finally, the agrin-LRP4
interaction could stimulate MuSK in astrocytes. We wondered whether MuSK activation is
necessary for agrin-promotion of Aβ uptake. Based on these results and considerations, we
hypothesized that LRP4 is critical to Aβ u...

## Key facts

- **NIH application ID:** 10072979
- **Project number:** 1RF1AG066526-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** WEN-CHENG XIONG
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,846,666
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072979

## Citation

> US National Institutes of Health, RePORTER application 10072979, LRP4 deficiency in Alzheimer's disease development (1RF1AG066526-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072979. Licensed CC0.

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