E-cadherin controls a wide array of cellular behaviors including cell-cell adhesion, differentiation and tissue development. Here we show that presenilin-1 (PS1), a protein involved in Alzheimer's disease, controls a gamma-secretase-like cleavage of E-cadherin. This cleavage is stimulated by apoptosis or calcium influx and occurs between human E-cadherin residues Leu731 and Arg732 at the membrane-cytoplasm interface. The PS1/gamma-secretase system cleaves both the full-length E-cadherin and a transmembrane C-terminal fragment, derived from a metalloproteinase cleavage after the E-cadherin ectodomain residue Pro700. The PS1/gamma-secretase cleavage dissociates E-cadherins, beta-catenin and alpha-catenin from the cytoskeleton, thus promoting disassembly of the E-cadherin-catenin adhesion complex. Furthermore, this cleavage releases the cytoplasmic E-cadherin to the cytosol and increases the levels of soluble beta- and alpha-catenins. Thus, the PS1/gamma-secretase system stimulates disassembly of the E-cadherin- catenin complex and increases the cytosolic pool of beta-catenin, a key regulator of the Wnt signaling pathway.

Studies from several laboratories have generated evidence suggesting that oxidative stress is involved in the pathogenesis of Alzheimer's disease (AD). The finding that the amyloid ␤ protein (A␤) has neurotoxic properties and that such effects are, in part, mediated by free radicals has provided insights into mechanisms of cell death in AD and an avenue to explore new therapeutic approaches. In this study we demonstrate that melatonin, a pineal hormone with recently established antioxidant properties, is remarkably effective in preventing death of cultured neuroblastoma cells as well as oxidative damage and intracellular Ca 2ϩ increases induced by a cytotoxic fragment of A␤. The effects of melatonin were extremely reproducible and corroborated by multiple quantitative methods, including cell viability studies by confocal laser microscopy, electron microscopy, and measurements of intracellular calcium levels. The importance of this finding is that, in contrast to conventional antioxidants, melatonin has a proposed physiological role in the aging process. Secretion levels of this hormone are decreased in aging and more severely reduced in AD. The reported phenomenon may be of therapeutic relevance in AD.

In MDCK cells, presenilin-1 (PS1) accumulates at intercellular contacts where it colocalizes with components of the cadherin-based adherens junctions. PS1 fragments form complexes with E-cadherin, beta-catenin, and alpha-catenin, all components of adherens junctions. In confluent MDCK cells, PS1 forms complexes with cell surface E-cadherin; disruption of Ca(2+)-dependent cell-cell contacts reduces surface PS1 and the levels of PS1-E-cadherin complexes. PS1 overexpression in human kidney cells enhances cell-cell adhesion. Together, these data show that PS1 incorporates into the cadherin/catenin adhesion system and regulates cell-cell adhesion. PS1 concentrates at intercellular contacts in epithelial tissue; in brain, it forms complexes with both E- and N-cadherin and concentrates at synaptic adhesions. That PS1 is a constituent of the cadherin/catenin complex makes that complex a potential target for PS1 FAD mutations.

Crocus sativus stigmas are one of the widely known spices (saffron) and consist of unusually polar carotenoids. Alzheimer's disease is characterized pathologically by deposition of amyloid beta-peptide (Abeta) fibrils. Oxidation is thought to promote Abeta fibril formation and deposition. To identify agents inhibiting the pathogenesis of Alzheimer's disease, we examined in vitro the antioxidant properties of extract of C. sativus stigmas and its effect on Abeta(1-40) fibrillogenesis. The antioxidant properties were determined by measuring the ferric-reducing antioxidant power and Trolox-equivalent antioxidant capacity, while its effects on Abeta-aggregation and fibrillogenesis were studied by thioflavine T-based fluorescence assay and by DNA binding shift assay. The water:methanol (50:50, v/v) extract of C. sativus stigmas possesses good antioxidant properties, higher than those of tomatoes and carrots, and inhibited Abeta fibrillogenesis in a concentration and time-dependent manner. The main carotenoid constituent, trans-crocin-4, the digentibiosyl ester of crocetin, inhibited Abeta fibrillogenesis at lower concentrations than dimethylcrocetin, revealing that the action of the carotenoid is enhanced by the presence of the sugars. Our findings suggest the possible use of C. sativus stigma constituents for inhibition of aggregation and deposition of Abeta in the human brain.

Here we show that presenilin-1 (PS1), a protein involved in Alzheimer's disease, binds directly to epithelial cadherin (E-cadherin). This binding is mediated by the large cytoplasmic loop of PS1 and requires the membrane-proximal cytoplasmic sequence 604 -615 of mature E-cadherin. This sequence is also required for E-cadherin binding of protein p120, a known regulator of cadherin-mediated cell adhesion. Using wild-type and PS1 knockout cells, we found that increasing PS1 levels suppresses p120͞E-cadherin binding, and increasing p120 levels suppresses PS1͞E-cadherin binding. Thus PS1 and p120 bind to and mutually compete for cellular E-cadherin. Furthermore, PS1 stimulates E-cadherin binding to ␤-and ␥-catenin, promotes cytoskeletal association of the cadherin͞catenin complexes, and increases Ca 2؉ -dependent cell-cell aggregation. Remarkably, PS1 familial Alzheimer disease mutant ⌬E9 increased neither the levels of cadherin͞catenin complexes nor cell aggregation, suggesting that this familial Alzheimer disease mutation interferes with cadherin-based cell-cell adhesion. These data identify PS1 as an E-cadherin-binding protein and a regulator of E-cadherin function in vivo.

Transmembrane proteins BRI2 and amyloid precursor protein (APP) co-localize with amyloid ␤ (A␤) lesions in sporadic Alzheimer disease and mutations in both precursor proteins are linked to early-onset familial cases of cerebral amyloidosis associated with dementia and/or cerebral hemorrhage. A specific interaction between BRI2 and APP was unveiled by immunoprecipitation experiments using transfected and non-transfected cells. The use of deletion mutants further revealed that stretches 648 -719 of APP751 and 46 -106 of BRI2, both inclusive of the full transmembrane domains, are sufficient for the interaction. Removal of most of the APP and BRI2 extracellular domains without affecting the interaction implies that both proteins interact when are expressed on the same cell membrane (cis) rather than on adjacent cells (trans). The presence of BRI2 had a modulatory effect on APP processing, specifically increasing the levels of cellular APP as well as ␤-secretasegenerated COOH-terminal fragments while decreasing the levels of ␣-secretase-generated COOH-terminal fragments as well as the secretion of total APP and A␤ peptides. Determining the precise molecular pathways affected by the specific binding between APP and BRI2 could result in the identification of common therapeutic targets for these sporadic and familial neurodegenerative disorders. A␤,1 a 39 -42-amino acid peptide of unknown biological function normally present in biological fluids, is also the main constituent of parenchymal and vascular amyloid deposits characteristic of Alzheimer disease (AD) (reviewed in Ref. 1). It is an internal fragment of the larger type-I transmembrane amyloid precursor protein APP (also referred as A␤PP), which exists in several isoforms of different length, ranging from 695 to 770 residues (2, 3). From all these APP isoforms, A␤ is normally generated by proteolytic processing through the sequential action of ␤-and ␥-secretases. Within amyloid lesions, a number of unrelated components collectively known as amyloid-associated proteins (amyloid P-component, ␣1-antichymotrypsin, apoE, apoJ, complement components, vitronectin, extracellular matrix proteins, and APP, among others) co-localize with fibrillar and non-fibrillar A␤, as shown by immunohistochemical studies (4 -10). It is not clear whether these proteins are important for the mechanism of amyloidogenesis or just innocent bystanders. Recently, it was reported that a novel protein BRI2 was abundant in dystrophic neurites, in senile plaques, and around vessels in ischemic lesions in AD and was also detected in Lewy neurites in cases of dementia with Lewy bodies and Parkinson disease (11). Of interest, mutations at or near the stop codon of BRI2 are associated with dementia and cerebellar ataxia in kindreds of British (12) and Danish (13) origin.BRI2 is a type-II transmembrane protein encoded by the single gene BRI2 (also known as ITM2B and E25B) located on the long arm of chromosome 13 (12, 14 -16). BRI2 belongs to an evolutionary conserved multigene family comprising at least...

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The Af3 peptide of Alzheimer disease is derived from the proteolytic processing of the amyloid precursor proteins (APP), which are considered type I transmembrane glycoproteins. Recently, however, soluble forms of full-length APP were also detected in several systems including chromaffin granules. In this report we used antisera specific