ArticleCommunications biology2024
Rescue of ApoE4-related lysosomal autophagic failure in Alzheimer's disease by targeted small molecules.
Article in Communications biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- Interleukin-1β-Induced Inflammatory Signaling and Myelin-Related Alterations in Oligodendroglia and Schwann Cells in Multiple Sclerosis: Modulatory Effects of Ibuprofen and Flurbiprofen.Current issues in molecular biology · 2026Article
- Protective mutations associated with APOE in Alzheimer's disease.Molecular psychiatry · 2026Review
- Zolpidem restores sleep and decreases amyloid in a mouse model.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Autophagy-lysosomal pathway in neurodegeneration.Molecular neurodegeneration advances · 2026Review
- APOE-Targeted Therapeutics for Alzheimer's Disease.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Review
- Zolpidem restores sleep and slows Alzheimer's progression in a mouse model.bioRxiv : the preprint server for biology · 2025Article
- From Better Diagnostics to Earlier Treatment: The Rapidly Evolving Alzheimer's Disease Landscape.Medicina (Kaunas, Lithuania) · 2025Review
- Article
- The Seminal Role of the Proinflammatory Cytokine IL-1β and Its Signaling Cascade in Glioblastoma Pathogenesis and the Therapeutic Effect of Interleukin-1β Receptor Antagonist (IL-1RA) and Tolcapone.International journal of molecular sciences · 2025Article
- The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.Cell death discovery · 2025Review
- Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.Basic research in cardiology · 2025Article
- Discovery of an ApoE4-targeted small-molecule SirT1 enhancer for the treatment of Alzheimer's disease.Scientific reports · 2025Article
- Proteostasis disruption and lipid dyshomeostasis in neurodegeneration: exploring common druggable targets across sporadic and monogenic disorders.Frontiers in molecular neuroscience · 2025Review
- Differentiating visceral sensory ganglion organoids from induced pluripotent stem cells.Nature methods · 2024Article
- Hiding in Plain Sight: FDA-Approved Cholesterol Drug Ezetimibe as a Treatment for Alzheimer's.Aging biology · 2024Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.