UCLA researchers from the Department of Neurology have identified and synthesized novel small molecules that enhance the levels of secreted clusterin protein, a protein that can targets a significant risk factor for the disease, and offering promising potential for the treatment of Alzheimer’s disease.
BACKGROUND: Alzheimer’s disease (AD) is a leading cause of dementia, affecting over 50 million people worldwide, and it ranks as the seventh-leading cause of death in the United States. In 2021, AD cost the United States $355 billion, and this cost is predicted to triple by 2050, making it an immense burden on healthcare systems. Although there are FDA-approved medications that provide symptom relief, they do little to slow or stop the disease’s progression. Recently, two new therapies received accelerated FDA approval after demonstrating the ability to decrease amyloid load in the brain but there was limited clinical improvement or delay in cognitive decline in AD patients. In addition, there were side effects such as brain swelling and microhemorrhages that raise concerns regarding their safety and long-term use. These approvals by the FDA illustrate the urgent need for additional therapies that can not only alleviate symptoms, but also slow the progression of AD, thus improving both lifespan and quality of life of individuals with AD. While the anti-amyloid therapies can reduce and Ab plaques in the brain, it likely that it still leaves the damaged neuronal circuits unaffected. sCLU enhancers have the potential to address this limitation and restore affected neurocircuits along with cognition. The sCLU enhancers can be administered early on in the disease progression or at later stages and in combination after treatment with the anti-amyloid therapy.
INNOVATION: Researchers at UCLA have identified small molecules candidate that increase the levels of the secreted isoform of the clusterin protein (sCLU), which protects the brain from accumulating toxic, misfolded proteins including Ab and p-tau. Importantly, a single nucleotide polymorphism (SNP) in the CLU gene is the third strongest genetic risk factor for late-onset AD. Researchers performed high-throughput screens (HTS) of UCLA compound libraries in vitro to identify compounds that increased secreted clusterin protein (sCLU) levels. In doing so, they identified hit compounds that were known epigenetic modulators which they further optimized by synthesizing novel analogs to ensure that the drugs would succeed in vivo. UCLA researchers then selected a promising preclinical candidate drug for short and long-term administration in a mouse models of AD. The compound was demonstrated to be brain permeable and increased sCLU quantities in the hippocampus. The long-term studies over 8 weeks shows the preclinical candidate can significantly reduce p-tau and improve memory. Subsequent proteomics and gene expression analysis were performed by researchers leading to (i) identification of AD-relevant proteins and (ii) enrichment of genes involved in metabolic and protein homeostasis, as well as synaptic plasticity. Lastly, in vitro studies performed by researchers demonstrated that this drug could improve neurite outgrowth in human induced pluripotent stem cell (iPSC)-derived neurons. In summary, UCLA researchers have identified small molecules that increase sCLU levels in the brain, expanding treatment options for AD and potentially other disorders.
POTENTIAL APPLICATIONS:
- Treatment to reduce the progression of AD, PD, ALS and other disorders such as diabetes and cardiovascular disease
- An in vitro method to promote neurite growth in iPSC-derived neurons
ADVANTAGES:
- The identified small molecules are FDA-approved
- The screened targets can have broader therapeutic effects such as for the treatment of diabetes and cardiovascular disease
DEVELOPMENT-TO-DATE: UCLA researchers have identified and synthesized novel small molecules that increase sCLU levels in vitro and in an in vivo mouse model. The in vitro studies also demonstrate that this drug can enhance neurite outgrowth in human iPSC-derived neurons.
Related Papers (from the inventors only) : Cohn, W., Campagna, J., Wi, D. et al. Discovery of a small molecule secreted clusterin enhancer that improves memory in Alzheimer’s disease mice. npj Drug Discov. 2, 7 (2025). https://doi.org/10.1038/s44386-025-00009-2
KEYWORDS: Small molecules, clusterin, Alzheimer’s disease, secreted clusterin, single nucleotide polymorphism, high-throughput screen, epigenetic modulators, medicinal chemistry optimization, drug discovery, hippocampus, proteomics, gene expression, metabolic, protein homeostasis, synaptic plasticity, neurite, induced pluripotent stem cells