Rescue of ApoE4-related lysosomal autophagic failure in Alzheimer's disease by targeted small molecules.

Communications biology 2024 Jan 08

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Homozygosity for the ε4 allele of APOE increases the odds of developing Alzheimer's by 12 to 15 times relative to the most common ε3;ε3 genotype, and its association with higher plaque loads comports with evidence that APOEε4 compromises autophagy. The ApoE4 protein specifically binds a cis element ("CLEAR") in the promoters of several autophagy genes to block their transcription. We used a multifaceted approach to identify a druggable site in ApoE4, and virtual screening of lead-like compounds identified small molecules that specifically bind to this site to impede ApoE4::DNA binding. We validated these molecules both in vitro and in vivo with models expressing ApoE4, including ApoE4 targeted-replacement mice. One compound was able to significantly restore transcription of several autophagy genes and protected against amyloid-like aggregation in a C. elegans AD model. Together, these findings provide proof-of-principle evidence for pharmacological remediation of lysosomal autophagy by ApoE4 via ApoE4-targeted lead molecules that represent a novel tack on neurodegenerative disorders. © 2024. The Author(s).

Citation

Meenakshisundaram Balasubramaniam, Jagadeesh Narasimhappagari, Ling Liu, Akshatha Ganne, Srinivas Ayyadevara, Ramani Atluri, Haarika Ayyadevara, Guy Caldwell, Robert J Shmookler Reis, Steven W Barger, W Sue T Griffin. Rescue of ApoE4-related lysosomal autophagic failure in Alzheimer's disease by targeted small molecules. Communications biology. 2024 Jan 08;7(1):60