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

Xavier Meckler, Jelita Roseman, Pritam Das, Haipeng Cheng, Susan Pei, Marcia Keat, Breanne Kassarjian, Todd E. Golde, Angèle T. Parent, Gopal Thinakaran

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Abstract

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 does not affect γ-secretase processing of amyloid precursor protein. To determine the importance of γ-secretase S-palmitoylation for Aβ 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 andPEN2or affect the localization of γ-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,weobserved a moderate, but significant, reduction in amyloid deposits in the forebrain of mice expressing S-palmitoylation-deficient γ-secretase subunits compared with mice overexpressing wild-type subunits, as well as a reduction in the levels of insoluble Aβ40-42. These results indicate that γ-secretase S-palmitoylation modulates Aβ deposition in the brain.

Original languageEnglish (US)
Pages (from-to)16160-16169
Number of pages10
JournalJournal of Neuroscience
Volume30
Issue number48
DOIs
StatePublished - Dec 1 2010

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Meckler, X., Roseman, J., Das, P., Cheng, H., Pei, S., Keat, M., Kassarjian, B., Golde, T. E., Parent, A. T., & Thinakaran, G. (2010). Reduced Alzheimer's disease β-amyloid deposition in transgenic mice expressing S-palmitoylation-deficient APH1aL and nicastrin. Journal of Neuroscience, 30(48), 16160-16169. https://doi.org/10.1523/JNEUROSCI.4436-10.2010