Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100

To differentiate multiple activities of presenilin 1 (PS1), we generated transgenic mice expressing two human PS1 alleles: one with the aspartate to alanine mutation at residue 257 (hPS1D257A) that impairs the proteolytic activity of PS1, and the other deleting amino acids 340 -371 of the hydrophilic loop sequence (hPS1⌬cat) essential for ␤-catenin interaction. We show here that although hPS1⌬cat is fully competent in rescuing the PS1-null lethal phenotype, hPS1D257A does not exhibit developmental activity. hPS1D257A also leads to the concurrent loss of the proteolytic processing of Notch and ␤-amyloid precursor protein (APP) and the generation of ␤-amyloid peptides (A␤). Further, by measuring the levels of endogenous A␤X-40 and A␤X-42 in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted A␤.

Section: Results Hps1⌬cat and Hps1d257a Exhibit Distinct Developmentamentioning

confidence: 99%

“…Sandwich ELISAs for quantifying mouse and human A␤ X-40 and A␤ X-42 were performed as described (25). Briefly, the 96-well immunoassay plates (Nunc) were coated with A␤ 40 and A␤ 42 end-specific monoclonal antibodies MBC40 and MBC42, respectively.…”

Section: Vector Construction and Generation Of Transgenic And Rescue mentioning

confidence: 99%

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

Xia

Wang

Sun

et al. 2002

“…␤-Catenin levels are significantly reduced in AD individuals bearing presenilin mutations (43) and active GSK3␤ accumulates in vivo in AD brains (44), thus affecting phosphorylation (45). Likewise, Wnt signaling may have an essential role in the processing of the amyloid precursor protein (46)(47)(48), as well as in the neurotoxicity of its derivative the amyloid ␤-peptide (45, 49-52). Therefore, the Wnt signaling cascade is a candidate for genetic studies aimed at understanding AD etiology.…”

Section: Discussionmentioning

confidence: 99%

Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease

Ferrari

Papassotiropoulos

Biechele

et al. 2007

258

224

Genome-wide linkage studies have defined a broad susceptibility region for late-onset Alzheimer's disease on chromosome 12, which contains the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) gene, a coreceptor for Wnt signaling. Here, we report the association between common LRP6 variants and late-onset Alzheimer's disease in a multicenter case-control series as well as in a large family-based series ascertained by the National Institute of Mental Health-National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-4 (APOE-4) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of LRP6 identified a putative risk haplotype, which includes a highly conserved coding sequence SNP: Ile-1062 3 Val. Functional analyses revealed that the associated allele Val-1062, an allele previously linked to low bone mass, has decreased ␤-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/␤-catenin signaling may be involved in this neurodegenerative disease.neurodegenerative ͉ LRP-6 ͉ single-nucleotide polymorphism ͉ APOE ͉ Wnt

“…TPKI͞GSK-3␤ plays a crucial role in A␤-triggered neuropathological cascades (19,24,30). Lithium has been suggested recently as a possible therapeutic reagent for AD, because of its ability to inhibit TPKI͞GSK-3␤ activity (31,32). Thus, we examined whether inhibition of TPKI͞GSK-3␤ by lithium protects neurons against ASPD toxicity.…”

Section: Morphology and Neurotoxicity Of Aspd Isolated From Sr-a␤1-40mentioning

confidence: 99%

Spherical aggregates of β-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3β

Hoshi

Sato

Matsumoto

et al. 2003

473

414

␤-Amyloid (A␤) acquires toxicity by self-aggregation. To identify and characterize the toxic form(s) of A␤ aggregates, we examined in vitro aggregation conditions by using large quantities of homogenous, chemically synthesized A␤1-40 peptide. We found that slow rotation of A␤1-40 solution reproducibly gave self-aggregated A␤1-40 containing a stable and highly toxic moiety. Examination of the aggregates purified by glycerol-gradient centrifugation by atomic force microscopy and transmission electron microscopy revealed that the toxic moiety is a perfect sphere, which we call amylospheroid (ASPD). Other A␤1-40 aggregates, including fibrils, were nontoxic. Correlation studies between toxicity and sphere size indicate that 10-to 15-nm ASPD was highly toxic, whereas ASPD <10 nm was nontoxic. A positive correlation between the toxicity and ASPD >10 nm also appeared to exist when A␤1-42 formed ASPD by slow rotation. However, A␤1-42-ASPD formed more rapidly, killed neurons at lower concentrations, and showed Ϸ100-fold-higher toxicity than A␤1-40-ASPD. The toxic ASPD was associated with SDS-resistant oligomeric bands in immunoblotting, which were absent in nontoxic ASPD. Because the formation of ASPD was not disturbed by pentapeptides that break ␤-sheet interactions, A␤ may form ASPD through a pathway that is at least partly distinct from that of fibril formation. Inhibition experiments with lithium suggest the involvement of tau protein kinase I͞gly-cogen synthase kinase-3␤ in the early stages of ASPD-induced neurodegeneration. Here we describe the identification and characterization of ASPD and discuss its possible role in the neurodegeneration in Alzheimer's disease.A 40-to 42-residue peptide named ␤-amyloid (A␤) is a major constituent of senile plaques in Alzheimer's disease (AD) (1). Although multiple pathways have been suggested to lead to AD, recent advances indicate a causal link between A␤ and AD (2), and this idea is supported further by findings that vaccination against A␤ ameliorates behavioral deficits in transgenic mice (3-5). Among various in vivo A␤ species, A␤ 1-42 generally is considered as the primary vehicle of toxicity, whereas A␤ 1-40 , a major species under physiological conditions, is considered less harmful and more resistant to the formation of oligomers than A␤ 1-42 (6). However, it remains controversial which A␤ species contributes predominantly to AD pathogenesis, because both in vitro and in vivo studies have confirmed toxicity of A␤ 1-40 aggregates (7,8).It has been widely accepted that toxicity of A␤ requires aggregation of native A␤ monomers (9-11). Besides fibrils, several types of nonfibrillar aggregates have been reported: A␤ 1-40 oligomers from dimers-hexamers (6, 12-14); a mixture of A␤ 1-42 oligomers named A␤-derived diffusible ligands (ADDLs), ranging from trimers-hexamers up to 24-mers (15); and fibril intermediates named protofibrils (PFs) (16,17). All of these aggregates are mixtures of A␤ oligomers with a variety in oligomer size, and precise morphological analysis of each A␤ a...