ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
Palmitoylation of amyloid precursor protein regulates amyloidogenic processing in lipid rafts.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers.
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Who cites it
110 citing papers in PubMed, 175 citations in OpenAlex.
- The role of protein palmitoylation in disease pathogenesis and therapeutic innovation.Annals of medicine · 2026Review
- Single-cell, spatial, and machine learning analyses identify ANKIB1 as an oligodendrocyte-anchored palmitoylation-associated candidate biomarker of Alzheimer's disease.Translational psychiatry · 2026Article
- Advances in Alzheimer's disease: mechanistic insights and therapeutic targets.Science China. Life sciences · 2026Review
- HDAC11 as a potential therapeutic target for Alzheimer's disease.Drug discovery today · 2026Review
- ProteinJournal of pharmaceutical analysis · 2026Review
- Review
- Sex-dependent rescue of memory and synaptic deficits in AD model mice by increasing PSD-95 palmitoylation.Communications biology · 2026Article
- Article
- The palmitoylation code in cell death signaling: from molecular mechanisms to therapeutic opportunities.Frontiers in cell and developmental biology · 2026Review
- The Causal Relationship Between Palmitoylation Genes and Parkinson's Disease: A Mendelian Randomization Study.Journal of molecular neuroscience : MN · 2025Article
- Profiling the landscape of cysteine posttranslational modifications in brain aging and neurodegeneration.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).International journal of molecular medicine · 2025Review
- Deciphering the Structural Biology of GFAP: Connotations of Its Potency in Presaging the Diagnosis for Traumatic Brain Injury and AD.Neurology international · 2025Review
- Palmitoylation: an emerging therapeutic target bridging physiology and disease.Cellular & molecular biology letters · 2025Review
- Amyloid β-Induced Inflammarafts in Alzheimer's Disease.International journal of molecular sciences · 2025Review
- Review
- Imaging lipid rafts reveals the principle of ApoE4-induced Aβ upregulation in human neurons.iScience · 2025Article
- Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.Frontiers in neuroscience · 2025Review
- Organelle abnormalities in Alzheimer's disease.Organelle (Tucson, Ariz.) · 2025Article
- Protein palmitoylation: an emerging regulator of inflammatory signaling and diseases.Frontiers in immunology · 2025Review
50 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Brains of patients affected by Alzheimer's disease (AD) contain large deposits of aggregated amyloid β-protein (Aβ). Only a small fraction of the amyloid precursor protein (APP) gives rise to Aβ. Here, we report that ∼10% of APP undergoes a post-translational lipid modification called palmitoylation. We identified the palmitoylation sites in APP at Cys¹⁸⁶ and Cys¹⁸⁷. Surprisingly, point mutations introduced into these cysteines caused nearly complete ER retention of APP. Thus, either APP palmitoylation or disulfide bridges involving these Cys residues appear to be required for ER exit of APP. In later compartments, palmitoylated APP (palAPP) was specifically enriched in lipid rafts. In vitro BACE1 cleavage assays using cell or mouse brain lipid rafts showed that APP palmitoylation enhanced BACE1-mediated processing of APP. Interestingly, we detected an age-dependent increase in endogenous mouse brain palAPP levels. Overexpression of selected DHHC palmitoyl acyltransferases increased palmitoylation of APP and doubled Aβ production, while two palmitoylation inhibitors reduced palAPP levels and APP processing. We have found previously that acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibition led to impaired APP processing. Here we demonstrate that pharmacological inhibition or genetic inactivation of ACAT decrease lipid raft palAPP levels by up to 76%, likely resulting in impaired APP processing. Together, our results indicate that APP palmitoylation enhances amyloidogenic processing by targeting APP to lipid rafts and enhancing its BACE1-mediated cleavage. Thus, inhibition of palAPP formation by ACAT or specific palmitoylation inhibitors would appear to be a valid strategy for prevention and/or treatment of AD.
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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.