# Screening for enhancers of secreted clusterin (sCLU) and evaluation in AD models

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $423,400

## Abstract

PROJECT SUMMARY/ABSTRACT
This proposal provides a unique opportunity to identify isoform-specific modulators of clusterin (CLU) and
evaluate its role in Alzheimer's disease (AD). Clusterin, also known as apolipoprotein J (Apo J) is a protein
originally identified in 1979. Several CLU gene variants are associated with AD and the SNP rs11136000C is
the third strongest genetic risk factor for Late Onset Alzheimer's disease (LOAD). There is evidence that
enhancing brain levels of sCLU will slow or reverse various molecular mechanisms underlying onset of the AD
pathophysiology. This is based on studies that show sCLU promoting the clearance of disease-causing
amyloid beta (Aβ) plaques, while reducing cellular stress responses such as oxidative stress and inflammation
known to lead to increased kinase activity such as GSK-3β and increased hyperphosphorylated tau involved in
progression of AD. Interestingly, the CLU gene variants that confer increased susceptibility to LOAD also
reduce sCLU levels and result in increased Aβ deposition and tau neurofibrillary tangles and faster cognitive
decline relative to non-carriers. In this proposal a comprehensive research program will be undertaken to
identify potent, brain permeable, small molecules that increase levels of sCLU and modulate biomarkers in AD
models. This will be accomplished using high throughput screening (HTS) to identify `hits' with potent sCLU
enhancing ability, drug-like properties, brain permeability in pharmacokinetics (PK) analyses to guide
compound selection for further testing and mechanism-of-action (MOA) studies in iPSC derived neurons and
ex-vivo models of AD. In Aim1 we will screen for compounds that increase extracellular concentrations of
sCLU. UCLA's large compound library will be screened by using fully automated liquid handling devices and
analytical instruments to identify molecules that increase sCLU levels. For these experiments, sensitive and
readily formattable AlphaLISA based immunoassays will be optimized to detect different CLU isoforms. In
Aim2, we would conduct in-vitro ADME/T testing and in-vivo pharmacokinetics (PK) analyses to guide hit
selection including determination of sCLU enhancing potency, characterizing the physiochemical properties
including solubility, brain permeability and metabolic stability of candidate sCLU enhancing compounds. In
Aim3, we would conduct testing in induced pluripotent stem cells (iPSCs) derived neurons and ex-vivo brain
slices. The goal is to evaluate the effectiveness of sCLU enhancers with sufficient oral brain bioavailability and
half-life in AD patient-derived neurons as well as in ex-vivo organotypic brain slice cultures from the
hippocampi of an AD mouse model. In Aim4, we would identify molecular targets and cell signaling pathways
affected by prioritized hits. MOA studies involving target identification by photoaffinity-labeling/purification as
well as global and phosphoproteome analyses will be accomplished using state-of-the-...

## Key facts

- **NIH application ID:** 10195566
- **Project number:** 1R21AG072150-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Varghese John
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,400
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10195566

## Citation

> US National Institutes of Health, RePORTER application 10195566, Screening for enhancers of secreted clusterin (sCLU) and evaluation in AD models (1R21AG072150-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10195566. Licensed CC0.

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