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 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 and PEN2 or 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, we observed 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 Aβ(40-42). These results indicate that γ-secretase S-palmitoylation modulates Aβ deposition in the brain.

• Authors: Xavier Meckler, Jelita Roseman, Pritam Das, Haipeng Cheng, Susan Pei, Marcia Keat, Breanne Kassarjian, Todd E Golde, Angèle T Parent, Gopal Thinakaran
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 30 Issue 48 Pg. 16160-9 (Dec 01 2010) ISSN: 1529-2401 [Electronic] United States
• PMID: 21123562 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Membrane Glycoproteins
• Membrane Proteins
• Peptide Fragments
• amyloid beta-protein (40-42)
• nicastrin protein
• Amyloid Precursor Protein Secretases
• Endopeptidases
• Aph1a protein, mouse

Topics

• Alzheimer Disease (genetics, metabolism, pathology)
• Amino Acid Sequence
• Amyloid Precursor Protein Secretases (biosynthesis, deficiency, physiology)
• Amyloid beta-Peptides (antagonists & inhibitors, metabolism, physiology)
• Animals
• Endopeptidases (biosynthesis, deficiency, physiology)
• Lipoylation (genetics, physiology)
• Membrane Glycoproteins (biosynthesis, deficiency, physiology)
• Membrane Proteins
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Molecular Sequence Data
• Peptide Fragments (metabolism, physiology)
• Plaque, Amyloid (metabolism, pathology)