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Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease.
Proc Natl Acad Sci U S A. 2017 11 07; 114(45):E9665-E9674.PN

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.

Authors+Show Affiliations

Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110. Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110.Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110. Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110.Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093.Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093.Department of Neurobiology, The University of Chicago, Chicago, IL 60637. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110. Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110.Department of Neurobiology, The University of Chicago, Chicago, IL 60637; gopal@uchicago.edu. Department of Neurology, The University of Chicago, Chicago, IL 60637. Department of Pathology, The University of Chicago, Chicago, IL 60637.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29078331

Citation

Andrew, Robert J., et al. "Lack of BACE1 S-palmitoylation Reduces Amyloid Burden and Mitigates Memory Deficits in Transgenic Mouse Models of Alzheimer's Disease." Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 45, 2017, pp. E9665-E9674.
Andrew RJ, Fernandez CG, Stanley M, et al. Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease. Proc Natl Acad Sci U S A. 2017;114(45):E9665-E9674.
Andrew, R. J., Fernandez, C. G., Stanley, M., Jiang, H., Nguyen, P., Rice, R. C., Buggia-Prévot, V., De Rossi, P., Vetrivel, K. S., Lamb, R., Argemi, A., Allaert, E. S., Rathbun, E. M., Krause, S. V., Wagner, S. L., Parent, A. T., Holtzman, D. M., & Thinakaran, G. (2017). Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 114(45), E9665-E9674. https://doi.org/10.1073/pnas.1708568114
Andrew RJ, et al. Lack of BACE1 S-palmitoylation Reduces Amyloid Burden and Mitigates Memory Deficits in Transgenic Mouse Models of Alzheimer's Disease. Proc Natl Acad Sci U S A. 2017 11 7;114(45):E9665-E9674. PubMed PMID: 29078331.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease. AU - Andrew,Robert J, AU - Fernandez,Celia G, AU - Stanley,Molly, AU - Jiang,Hong, AU - Nguyen,Phuong, AU - Rice,Richard C, AU - Buggia-Prévot,Virginie, AU - De Rossi,Pierre, AU - Vetrivel,Kulandaivelu S, AU - Lamb,Raza, AU - Argemi,Arnau, AU - Allaert,Emilie S, AU - Rathbun,Elle M, AU - Krause,Sofia V, AU - Wagner,Steven L, AU - Parent,Angèle T, AU - Holtzman,David M, AU - Thinakaran,Gopal, Y1 - 2017/10/23/ PY - 2017/10/29/pubmed PY - 2018/6/19/medline PY - 2017/10/29/entrez KW - 5XFAD KW - PDAPP KW - axonal transport KW - dystrophic neurite KW - neurodegeneration SP - E9665 EP - E9674 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 114 IS - 45 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/29078331/Lack_of_BACE1_S_palmitoylation_reduces_amyloid_burden_and_mitigates_memory_deficits_in_transgenic_mouse_models_of_Alzheimer's_disease_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=29078331 DB - PRIME DP - Unbound Medicine ER -