# Novel roles for the Alzheimer's Disease (AD) risk gene, SORLA in neuroprotection in AD

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2022 · $681,307

## Abstract

PROJECT SUMMARY
SORLA is a genetic risk factor for Alzheimer’s disease (AD) identified through GWAS analysis. Although
SORLA has been shown to regulate APP trafficking and consequent Aβ generation, a normal biological
function for SORLA remains elusive. It is likely that SORLA mediates additional neuroprotective effects in AD;
given that numerous mutational coding variants have been identified in SORLA through whole exome
sequencing in AD cohorts, these mutations may perturb SORLA-dependent neuroprotection, either through
functional protein-protein interaction or SORLA localization. Our preliminary results indicate that SORLA exerts
neuroprotective effects by binding and inhibiting the activation of putative Aβ receptors such as EphA4 to limit
synaptotoxic EphA4 activation and cognitive impairment with Aβ exposure. We also demonstrate a role for
SORLA in enhancing neurite outgrowth and regeneration, and that neurotrophic SORLA-binding ligands
(“SORLA ligands”) such as head activator (HA) and neurotensin (NT) peptides can mediate neurite
enhancement in a SORLA-dependent manner. Together, these results implicate new roles for SORLA in
enhancing synaptic function, neurite outgrowth and regeneration. The overall objective of this study is to
characterize mechanisms underlying SORLA-dependent resistance to Aβ synaptotoxicity, and to determine
whether enhancing SORLA-mediated neuroprotective mechanisms can ameliorate synaptic and cognitive
impairment in Aβ-dependent neurodegenerative models such as AD and Down Syndrome (DS).
Interactions between SORLA and receptors that modulate synaptic function such as EphA4 and TrkB, likely
drive SORLA-dependent neuroprotection with Aβ synaptotoxicity. Using a library comprising a comprehensive
set of SORLA-FLAG early and late onset AD-associated mutational variants, we will determine whether
mutations can affect SORLA interactions with TrkB, or neurotrophic ligands, and characterize differences in the
SORLA interactome in these variants. Given that SORLA can enhance synaptic function with Aβ exposure, we
will determine whether neurotrophic SORLA ligands can enhance synaptic LTP response and cognitive
function with stereotactic Aβ co-injection into the hippocampus. We also present evidence that similar to AD,
aged DS mouse models show similar EphA4 activation, indicating that EphA4 may drive some aspects of
synaptotoxicity in DS. We will determine whether transgenic SORLA overexpression in DS mouse models can
reduce synaptotoxic EphA4 activation and synaptic/cognitive impairment in a DS mouse model. Lastly, we will
determine whether SORLA neuroprotection through stereotactic delivery of SORLA ligands can reverse or
attenuate synaptic/cognitive impairment in AD mouse models and use bivalent SORLA/EphA4 crosslinking
peptides to determine whether reinforcing neuroprotective SORLA/EphA4 interactions can confer
synaptoprotective effects in AD mice. Together, these results will implicate new roles for SORLA in
neuroprotec...

## Key facts

- **NIH application ID:** 10404609
- **Project number:** 5R01AG061875-05
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Timothy Yikai Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $681,307
- **Award type:** 5
- **Project period:** 2018-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404609

## Citation

> US National Institutes of Health, RePORTER application 10404609, Novel roles for the Alzheimer's Disease (AD) risk gene, SORLA in neuroprotection in AD (5R01AG061875-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10404609. Licensed CC0.

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