ArticleProceedings of the National Academy of Sciences of the United States of America2017
Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 69 citations in OpenAlex.
- Review
- Protein Palmitoylation as a Molecular Switch Linking Regulated Cell Death and Disease.Biomolecules · 2026Review
- Review
- Sex-dependent rescue of memory and synaptic deficits in AD model mice by increasing PSD-95 palmitoylation.Communications biology · 2026Article
- Recent advances in S-palmitoylation and its emerging roles in human diseases.Journal of hematology & oncology · 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
- Review
- Palmitoylation-related gene ZDHHC22 as a potential diagnostic and immunomodulatory target in Alzheimer's disease: insights from machine learning analyses and WGCNA.European journal of medical research · 2025Article
- Protein palmitoylation: an emerging regulator of inflammatory signaling and diseases.Frontiers in immunology · 2025Review
- Inhibition of zDHHC7-driven protein S-palmitoylation prevents cognitive deficits in an experimental model of Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons.Nature communications · 2024Article
- Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Review
- Cholesterol and Lipid Rafts in the Biogenesis of Amyloid-β Protein and Alzheimer's Disease.Annual review of biophysics · 2024Review
- Reduction of DHHC5-mediated beclin 1 S-palmitoylation underlies autophagy decline in aging.Nature structural & molecular biology · 2024Article
- Direct regulation of the voltage sensor of HCN channels by membrane lipid compartmentalization.Nature communications · 2023Article
- Characterizing the transmembrane domains of ADAM10 and BACE1 and the impact of membrane composition.Biophysical journal · 2023Article
- Amyloid Precursor Protein and Alzheimer's Disease.International journal of molecular sciences · 2023Review
- Roles of protein post-translational modifications in glucose and lipid metabolism: mechanisms and perspectives.Molecular medicine (Cambridge, Mass.) · 2023Review
- The role of s-palmitoylation in neurological diseases: implication for zDHHC family.Frontiers in pharmacology · 2023Review
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Authors and funding
18 authors at 3 institutions in 1 country.
Funding
Abstract
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by pathological brain lesions and a decline in cognitive function. β-Amyloid peptides (Aβ), derived from proteolytic processing of amyloid precursor protein (APP), play a central role in AD pathogenesis. β-Site APP cleaving enzyme 1 (BACE1), the transmembrane aspartyl protease which initiates Aβ production, is axonally transported in neurons and accumulates in dystrophic neurites near cerebral amyloid deposits in AD. BACE1 is modified by S-palmitoylation at four juxtamembrane cysteine residues. S-palmitoylation is a dynamic posttranslational modification that is important for trafficking and function of several synaptic proteins. Here, we investigated the in vivo significance of BACE1 S-palmitoylation through the analysis of knock-in mice with cysteine-to-alanine substitution at the palmitoylated residues (4CA mice). BACE1 expression, as well as processing of APP and other neuronal substrates, was unaltered in 4CA mice despite the lack of BACE1 S-palmitoylation and reduced lipid raft association. Whereas steady-state Aβ levels were similar, synaptic activity-induced endogenous Aβ production was not observed in 4CA mice. Furthermore, we report a significant reduction of cerebral amyloid burden and BACE1 accumulation in dystrophic neurites in the absence of BACE1 S-palmitoylation in mouse models of AD amyloidosis. Studies in cultured neurons suggest that S-palmitoylation is required for dendritic spine localization and axonal targeting of BACE1. Finally, the lack of BACE1 S-palmitoylation mitigates cognitive deficits in 5XFAD mice. Using transgenic mouse models, these results demonstrate that intrinsic posttranslational S-palmitoylation of BACE1 has a significant impact on amyloid pathogenesis and the consequent cognitive decline.
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