Presenilin 1 Facilitates the Constitutive Turnover of β-Catenin: Differential Activity of Alzheimer’s Disease–Linked PS1 Mutants in the β-Catenin–Signaling Pathway

Abstract

Although an association between the product of the familial Alzheimer's disease (FAD) gene, presenilin 1 (PS1), and beta-catenin has been reported recently, the cellular consequences of this interaction are unknown. Here, we show that both the full length and the C-terminal fragment of wild-type or FAD mutant PS1 interact with beta-catenin from transfected cells and brains of transgenic mice, whereas E-cadherin and adenomatous polyposis coli (APC) are not detected in this complex. Inducible overexpression of PS1 led to increased association of beta-catenin with glycogen synthase kinase-3beta (GSK-3beta), a negative regulator of beta-catenin, and accelerated the turnover of endogenous beta-catenin. In support of this finding, the beta-catenin half-life was dramatically longer in fibroblasts deficient in PS1, and this phenotype was completely rescued by replacement of PS1, demonstrating that PS1 normally stimulates the degradation of beta-catenin. In contrast, overexpression of FAD-linked PS1 mutants (M146L and DeltaX9) failed to enhance the association between GSK-3beta and beta-catenin and interfered with the constitutive turnover of beta-catenin. In vivo confirmation was demonstrated in the brains of transgenic mice in which the expression of the M146L mutant PS1 was correlated with increased steady-state levels of endogenous beta-catenin. Thus, our results indicate that PS1 normally promotes the turnover of beta-catenin, whereas PS1 mutants partially interfere with this process, possibly by failing to recruit GSK-3beta into the PS1-beta-catenin complex. These findings raise the intriguing possibility that PS1-beta-catenin interactions and subsequent activities may be consequential for the pathogenesis of AD.

The aspartate-257 of presenilin 1 is indispensable for mouse development and production of β-amyloid peptides through β-catenin-independent mechanisms

“…All transgenic lines were viable and overtly normal. Consistent with earlier reports (14,26), hPS1⌬cat protein was endoproteolytically cleaved to generate an NTF indistinguishable from that of wild-type hPS1 and a truncated CTF ( Fig. 1 B and D).…”

“…This reasoning is corroborated by the fact that PS1 is known to interact with numerous proteins through its hydrophilic loop domain, in particular ␤-catenin, a molecule essential in Wnt͞wingless signaling and cell adhesion (13). PS1 has been shown to downregulate ␤-catenin stability and signaling and this activity requires the interaction of the two molecules (14)(15)(16). It also associates with the cadherin͞catenin complex at adhesive junctions of epithelial cells and at synaptic contacts of the CNS, suggesting a functional role of PS1 in cell-cell interaction (17).…”

Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

“…g-Secretase has many substrate proteins in addition to E-cadherin including amyloid precursor protein (APP), the Wnt/b-catenin pathway, and the Notch family (Notch 1-4; refs. [29][30][31][32][33]. Notch activation involves the proteolytic cleavage of the Notch ligand/receptor complex by g-secretase to release the Notch intracellular domain (NICD) that translocates to the nucleus and upregulates expression of a number of different downstream genes (34).…”

The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

“…Interestingly, FADlinked mutations (M146L, ⌬exon9, C263R, and P246L) have been found to impair this ␥-secretase-independent activity as well, resulting in enhanced ␤-catenin stability and ␤-catenin-dependent signaling (26,27). Recently, PS holoproteins were found to function as passive ER calcium leak channels independent of ␥-secretase activity, and two FAD-associated mutations (PS1 M146V and PS2 N141L) impaired this function (28).…”