# Reelin and Receptor Splicing in Alzheimer's Disease

> **NIH NIH RF1** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2024 · $2,431,261

## Abstract

Reelin signaling enhances hippocampal synaptic plasticity and increasing evidence
suggests Reelin serves a neuroprotective role in Alzheimer’s disease (AD). Reelin delays AD hallmarks
including amyloid plaque formation, tau hyperphosphorylation, and cognitive deficits, contributing to remarkable
resilience against AD. Reelin’s ability to enhance synaptic plasticity is dependent on its obligate
APOER2/VLDLR receptors that are prone to high degree of alternative splicing. We uncovered a diverse range
of human full-length APOER2 splice transcripts in postmortem AD brains and age-matched controls. Most of
the splicing events occur in functionally important domains such as the ligand-binding domains where Reelin
binds suggesting variation in ligand-receptor interactions and functional consequences related to Reelin
signaling; however, this has not been explored. The project includes three aims. Aim 1 seeks to determine if
alternative splicing of APOER2 and VLDLR, the obligate receptors of Reelin, impacts AD risk. Aim 2 will assess
the functional consequences of receptor splice variants on Reelin binding and signaling, proposing that specific
interactions may either protect against or increase AD risk. Finally, Aim 3 will explore the mechanism of Reelin's
resilience in AD-associated tau pathology, utilizing a CRISPR activation strategy to increase endogenous Reelin
expression with the goal of reversing tau pathology-related deficits. This project, poised to deliver high-impact
insights of resilient AD genes and promising therapeutics in the AD field.

## Key facts

- **NIH application ID:** 10856480
- **Project number:** 1RF1AG086313-01
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** Uwe Beffert
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,431,261
- **Award type:** 1
- **Project period:** 2024-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10856480

## Citation

> US National Institutes of Health, RePORTER application 10856480, Reelin and Receptor Splicing in Alzheimer's Disease (1RF1AG086313-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10856480. Licensed CC0.

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