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Reduced Alzheimer's disease ß-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin.


ABSTRACT: Sequential cleavage of amyloid precursor protein by ?- and ?-secretases generates ?-amyloid peptides (A?), which accumulate in the brains of patients with Alzheimer's disease. We recently identified S-palmitoylation of two ?-secretase subunits, APH1 and nicastrin. S-Palmitoylation is an essential posttranslational modification for the proper trafficking and function of many neuronal proteins. In cultured cell lines, lack of S-palmitoylation causes instability of nascent APH1 and nicastrin but does not affect ?-secretase processing of amyloid precursor protein. To determine the importance of ?-secretase S-palmitoylation for A? deposition in the brain, we generated transgenic mice coexpressing human wild-type or S-palmitoylation-deficient APH1aL and nicastrin in neurons in the forebrain. We found that lack of S-palmitoylation did not impair the ability of APH1aL and nicastrin to form enzymatically active protein complexes with endogenous presenilin 1 and PEN2 or affect the localization of ?-secretase subunits in dendrites and axons of cortical neurons. When we crossed these mice with 85Dbo transgenic mice, which coexpress familial Alzheimer's disease-causing amyloid precursor protein and presenilin 1 variants, we found that coexpression of wild-type or mutant APH1aL and nicastrin led to marked stabilization of transgenic presenilin 1 in the brains of double-transgenic mice. Interestingly, we observed a moderate, but significant, reduction in amyloid deposits in the forebrain of mice expressing S-palmitoylation-deficient ?-secretase subunits compared with mice overexpressing wild-type subunits, as well as a reduction in the levels of insoluble A?(40-42). These results indicate that ?-secretase S-palmitoylation modulates A? deposition in the brain.

SUBMITTER: Meckler X 

PROVIDER: S-EPMC2999009 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Reduced Alzheimer's disease ß-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin.

Meckler Xavier X   Roseman Jelita J   Das Pritam P   Cheng Haipeng H   Pei Susan S   Keat Marcia M   Kassarjian Breanne B   Golde Todd E TE   Parent Angèle T AT   Thinakaran Gopal G  

The Journal of neuroscience : the official journal of the Society for Neuroscience 20101201 48


Sequential cleavage of amyloid precursor protein by β- and γ-secretases generates β-amyloid peptides (Aβ), which accumulate in the brains of patients with Alzheimer's disease. We recently identified S-palmitoylation of two γ-secretase subunits, APH1 and nicastrin. S-Palmitoylation is an essential posttranslational modification for the proper trafficking and function of many neuronal proteins. In cultured cell lines, lack of S-palmitoylation causes instability of nascent APH1 and nicastrin but do  ...[more]

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