Differential display analysis of presenilin 1-deficient mouse brains.
Missense mutations in presenilin 1 (PS1) gene are the most common cause of early onset familial Alzheimer's disease (FAD). AD pathogenic PS1 mutations result in elevated gamma-secretase cleavage of APP and diminished S3-site cleavage of Notch. We have previously described a PS1-hypomorphic mouse line that could survive postnatally with markedly reduced gamma-secretase cleavage of APP and S3-site cleavage of Notch, resulting in a Notch developmental phenotype similar to PS1-null mice. This model was exploited to identify genes whose expression is altered due to the loss of PS1. A global gene expression study by differential display was performed on whole brains of PS1-hypomorphic mice and their wild type siblings. In total, more than 16,000 bands corresponding to cDNAs were compared between the mutant and wild-type brains. This analysis identified 19 cDNAs showing significantly altered expression resulting from PS1 deficiency. Four of the identified cDNAs corresponded to genes that could be associated with AD or presenilin function. Hypoxia inducible factor 1a (Hif1a), NPRAP (delta-catenin) and cell division cycle 10 (CDC10) showed significantly reduced expression in the PS1-hypomorphic compared to wild-type brains, whereas expression of nucleoside diphosphate kinase sub-unit A (NDPK-A) was markedly elevated in the respective brains. Clarification of the possible role of these genes in AD and the basis for their differential expression induced by PS1-deficiency may provide insight into the disease, presenilin function and consequences of its loss, as well as possible deleterious effects of AD therapeutics aimed at inhibiting PS1.
Liauw
Jennifer
J
Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Nguyen
Van
V
Huang
Jean
J
St George-Hyslop
Peter
P
Rozmahel
Richard
R
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction / Q000379:methods; D053764:Presenilin-1
D008565:Membrane Proteins; D053764:Presenilin-1