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Familial Alzheimer's disease (FAD) is caused by mutations in amyloid precursor protein or presenilins (PS1, PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca 2+ ) homeostasis by mechanisms proximal to and independent of amyloid production, although the molecular details are controversial. Here, we demonstrate that several FAD-causing PS mutants enhance gating of the inositol trisphosphate receptor (InsP 3 R) Ca 2+ release channel by a gain-offunction effect that mirrors the genetics of FAD and is independent of secretase activity. In contrast, wild type PS or PS mutants that cause frontotemporal dementia have no such effect. FAD PS alter InsP 3 R channel gating by modal switching. Recordings of endogenous InsP 3 R in lymphoblasts derived from individuals with FAD or cortical neurons of asymptomatic PS1-AD mice revealed they have higher occupancy in a high open probability burst mode compared to that of InsP 3 R in cells with wild-type PS, resulting in enhanced Ca 2+ signaling. These results indicate that exaggerated Ca 2+ signaling through InsP 3 R-PS interaction is a disease-specific and robust proximal mechanism in FAD.

A dinucleotide repeat polymorphism in a tau intron was identified and used in a case-control study to analyze the genetic association of tau with several neurodegenerative diseases with tau pathology. Subjects with the homozygous tau AO alleles were excessively represented in the progressive supranuclear palsy (PSP) group, compared with the age-matched healthy control group. Consequently, this allele is more frequently found in PSP than in a group of healthy subjects. This trend was not found in Alzheimer's disease or parkinsonism-dementia complex of Guam, both of which are accompanied by major tau pathology. The result suggests a possible involvement of tau in the pathogenesis of PSP.

The Alzheimer's disease-linked gene presenilin 1 (PS1) is required for intramembrane proteolysis of APP and Notch. In addition, recent observations strongly implicate PS1 as a negative regulator of the Wnt/beta-catenin signaling pathway, although the mechanism underlying this activity is unknown. Here, we show that presenilin functions as a scaffold that rapidly couples beta-catenin phosphorylation through two sequential kinase activities independent of the Wnt-regulated Axin/CK1alpha complex. Thus, presenilin deficiency results in increased beta-catenin stability in vitro and in vivo by disconnecting the stepwise phosphorylation of beta-catenin, both in the presence and absence of Wnt stimulation. These findings highlight an aspect of beta-catenin regulation outside of the canonical Wnt-regulated pathway and a function of presenilin separate from intramembrane proteolysis.