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

Lipophagy, the selective degradation of lipid droplets (LDs) by autophagy, has the potential to ameliorate neurodegenerative diseases such as Parkinson's (PD) and Alzheimer's (AD), wherein LD accumulation has been linked to the exacerbation of the proteinopathy component of neurodegeneration. Pharmacological lipophagy inducers remain scarce. We previously identified AA-20 as a novel autophagy activator that acts independently of mTORC1 inhibition, thereby providing a means of stimulating autophagy while avoiding the immunosuppressive side effects associated with direct mTORC1 inhibition. Prior work also showed that AA-20 treatment reduces PolyQ aggregate levels in several C. elegans tissues. Here, we demonstrate that AA-20 enhances LD recruitment to autophagosomes and promotes LD degradation via lysosomal acid lipase activation in murine hippocampal neuronal cells, consistent with lipophagy activation. In human Swedish Amyloid Precursor Protein mutated cerebral organoids, two weeks of AA-20 treatment normalized aberrant lipidomic profiles by selectively reducing various disease-associated lipids, while also correcting the AD-associated electrical hyperexcitability phenotype. Moreover, we identified cyclin-dependent kinase 5 (CDK5), a neuronal kinase linked to AD hyperexcitability and PD pathology, as a target of AA-20. AA-20-induced autophagy and lipid clearance in HT22 cells require CDK5. In a neuronal seeding model of α-synuclein pathology, AA-20 reduced pS129-α-synuclein levels. Collectively, these findings indicate AA-20 can promote lipophagic clearance of LDs and mitigate multiple cellular phenotypes associated with lipidopathy and proteinopathy in neurodegenerative disease models.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-11-02
DOI
https://doi.org/10.64898/2026.10.30.760220
Primary Topic
Autophagy in Disease and Therapy
Type
preprint

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preprint

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

Karina Nugroho, Derek J. Rhoades, Caroline A. Cuoco, Carl T. Ash et al.
bioRxiv (Cold Spring Harbor Laboratory)
Autophagy in Disease and Therapy
preprint

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

Karina Nugroho, Derek J. Rhoades, Caroline A. Cuoco, Carl T. Ash, Anne‐Laure Mahul‐Mellier, Sarah Ly, Patricia Martínez-Botía, Miguel A. Prado, Malene Hansen, João A. Paulo, Ee Phie Tan, Oren L. Lederberg, Yin Wu, Stuart A. Lipton, Stefano Forli, Evan T. Powers, Steven P. Gygi, Jeffery W. Kelly, Hilal Ahmed Lashuel, Sergio R. Labra, Lynée A. Massey, Christian M. Cole, Michael Petrascheck, Jadon Compher, Wen Ren, Dan Finley, Danny Garza, Mireya Almaraz, Lydia Ambaye, Zi Gao, Yuting Zhang, Alex Matthewson, Zainab Ahmed
preprint en

Abstract

Lipophagy, the selective degradation of lipid droplets (LDs) by autophagy, has the potential to ameliorate neurodegenerative diseases such as Parkinson's (PD) and Alzheimer's (AD), wherein LD accumulation has been linked to the exacerbation of the proteinopathy component of neurodegeneration. Pharmacological lipophagy inducers remain scarce. We previously identified AA-20 as a novel autophagy activator that acts independently of mTORC1 inhibition, thereby providing a means of stimulating autophagy while avoiding the immunosuppressive side effects associated with direct mTORC1 inhibition. Prior work also showed that AA-20 treatment reduces PolyQ aggregate levels in several C. elegans tissues. Here, we demonstrate that AA-20 enhances LD recruitment to autophagosomes and promotes LD degradation via lysosomal acid lipase activation in murine hippocampal neuronal cells, consistent with lipophagy activation. In human Swedish Amyloid Precursor Protein mutated cerebral organoids, two weeks of AA-20 treatment normalized aberrant lipidomic profiles by selectively reducing various disease-associated lipids, while also correcting the AD-associated electrical hyperexcitability phenotype. Moreover, we identified cyclin-dependent kinase 5 (CDK5), a neuronal kinase linked to AD hyperexcitability and PD pathology, as a target of AA-20. AA-20-induced autophagy and lipid clearance in HT22 cells require CDK5. In a neuronal seeding model of α-synuclein pathology, AA-20 reduced pS129-α-synuclein levels. Collectively, these findings indicate AA-20 can promote lipophagic clearance of LDs and mitigate multiple cellular phenotypes associated with lipidopathy and proteinopathy in neurodegenerative disease models.

bioRxiv (Cold Spring Harbor Laboratory)
Scripps Research Institute (US), Buck Institute for Research on Aging (US), Harvard University (US), Instituto de Investigación Sanitaria del Principado de Asturias (ES), École Polytechnique Fédérale de Lausanne (CH)
California Institute for Regenerative Medicine, Instituto de Salud Carlos III, National Institute on Aging, Freedom Together Foundation
Good health and well-being
Autophagy in Disease and Therapy
DOIOpen Access PDFOpenAlex
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