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

Sequential cleavage of amyloid precursor protein by ß- and γ-secretases generates ß-amyloid peptides (Aß), 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 Aß 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 Aß(40-42). These results indicate that γ-secretase S-palmitoylation modulates Aß deposition in the brain.

Coupling genetic and ecological-niche models to examine how past population distributions contribute to divergence.

Understanding the impact of climate-induced distributional shifts on species divergence, like those accompanying the Pleistocene glacial cycles [1, 2], requires tools that explicitly incorporate the geographic configuration of past distributions into analyses of genetic differentiation. Depending on the historical distribution of species, genetic differences may accumulate among ancestral source populations, but there is long-standing debate whether displacements into glacial refugia promoted divergence. Here we integrate coalescent-based genetic models [3, 4] with ecological-niche modeling [5, 6] to generate expectations for patterns of genetic variation based on an inferred past distribution of a species. Reconstruction of the distribution of a montane grasshopper species during the last glacial maximum suggests that Melanoplus marshalli populations from the sky islands of Colorado and Utah were likely colonized from multiple ancestral source populations. The genetic analyses provide compelling evidence that the historical distribution of M. marshalli-namely, spatial separation of multiple refugia-was conducive to genetic differentiation. The coupling of genetic and ecological-niche modeling provides a new and flexible tool for integrating paleoenvironmental details into species-specific predictions of population structure that can increase our understanding of why the glacial cycles promoted speciation in some taxa and yet inhibited diversification in others [7, 8].