Autophagy activator AA-20 engages CDK5 to promote lipophagy and improve neurodegeneration-associated phenotypes

AA-20 promotes lipophagy in murine hippocampal neuronal cells by enhancing lipid droplet recruitment to autophagosomes and enabling lysosomal acid lipase–dependent lipid degradation.

• Why it matters: Lipid droplet accumulation is linked to worsening proteinopathy in neurodegenerative diseases, yet pharmacological lipophagy inducers are limited.
• What they did: AA-20 was tested in murine hippocampal neuronal cells for lipophagy readouts, and in human Swedish Amyloid Precursor Protein mutated cerebral organoids for lipidomic normalization and electrical hyperexcitability after two weeks.
• The result: AA-20 normalized aberrant lipidomic profiles and corrected AD-associated electrical hyperexcitability in the organoids, and in HT22 cells and a neuronal -synuclein seeding model it required CDK5 and reduced pS129--synuclein levels.

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