# Screening for SORLA enhancers and evaluation in AD models

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $429,000

## Abstract

Alzheimer's disease (AD) afflicts more than 5.8 million people in the US at an estimated cost greater than $200
billion per year. Currently approved drugs offer only short-term symptomatic relief but do not alter disease
progression. The neuritic plaques that are a hallmark of AD brain result from increased generation and/or
decreased clearance of the amyloid beta peptide (Aβ) which originates from amyloid precursor protein (APP).
Processing of APP occurs by two pathways ─ sequential β-secretase and γ-secretase cleavages to generate
soluble amyloid precursor protein beta (sAPPβ) and Aβ or cleavage by α-secretase to generate soluble
amyloid precursor protein alpha (sAPPα), a pro-cognitive peptide that may prevent disease progression in AD.
Sorting protein-related receptor with A-type repeats (SORLA) plays a key role in modulating the intracellular
trafficking of APP through the secretory and endocytic pathways that regulates its commitment towards the
amyloidogenic or non-amyloidogenic processing and constitutes a promising target which could be modulated
by innovative therapeutic strategies to enhance sAPPα. SORLA is significantly reduced in brain tissue from
late-onset AD (LOAD) patients (Scherzer et al. 2004), numerous studies have linked impaired SORLA with an
increased risk of sporadic AD (Campion et al. 2019). Importantly, SORLA overexpression has been shown to
increase sAPPα and reduce Aβ in models of AD. Mechanisms by which SORLA regulates APP processing
include interaction with APP in the trans-Golgi thereby limiting the pool of endosomal APP available for
amyloidogenic proteolysis; inhibition of the dimerization of APP, thus reducing β-secretase cleavage; and its
binding Aβ through the VPS10P domain, targeting it to lysosomes for degradation. Here, we propose utilizing
our high-throughput screening (HTS) assay, iterative screening flowscheme, and the large UCLA compound
library to identify compounds that enhance SORLA protein levels in neurons. In the primary HTS screen, “hits”
that increase SORLA will be identified. In the secondary screen validated hits would be evaluated in neuronal
cells. Prioritized hits will be evaluated for effects on SORLA in patient iPSC's and ex vivo in organotypic slice
cultures. Brain penetrance on promising hits planned to be done by in vivo pharmacokinetic (PK) analysis.
Finally, we will determine the mechanisms/target by which hits induce SORLA enhancement using the CEREP
Bioprint profile panel, affinity purification/proteomics and in silico target identification using the similarity
ensemble approach. In Aim1, we plan to conduct high throughput screening (HTS) in CHO-7W cells to identify
`hits' that enhance SORLA levels and validate them in SH-SY5Y cells. In Aim2, we will conduct testing of
validated hits for ability to enhance SORLA and sAPPalpha levels in primary neuronal cultures and in AD
patient derived iPSC. In Aim3, we will evaluate prioritized hits in organotypic slice cultures from hippocampal
ti...

## Key facts

- **NIH application ID:** 9959093
- **Project number:** 1R21AG067461-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Varghese John
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2020-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959093

## Citation

> US National Institutes of Health, RePORTER application 9959093, Screening for SORLA enhancers and evaluation in AD models (1R21AG067461-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9959093. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*