title: Complexing Aβ prevents the cellular anomalies induced by the Peptide alone.
abstract: Retention of intracellular secreted APP (isAPP) can be provoked by the neurotoxic peptide Aβ. The latter decreases in the cerebrospinal fluid of Alzheimer's disease (AD) patients, as a consequence of its cerebral accumulation and deposition into senile plaques. Of similar relevance, secreted APP (sAPP) levels can be associated with AD. The studies here presented, reinforce the link between sAPP and Aβ and address putative therapeutic strategies. Laminin and gelsolin are potential candidates; both prevent Aβ fibril formation by complexing with Aβ, thus attenuating its neurotoxicity. We show that preincubation of Aβ with laminin and gelsolin has the effect of rendering it less potent to isAPP accumulation in cortical neurons. This appears to be related to a decrease in F-actin polymerization, whereas Aβ alone induces the polymerization. Further, Aβ decreases gelsolin levels, and the latter is involved in Aβ removal. Our data indicates that Aβ-laminin and Aβ-gelsolin complexes are less neurotoxic and also less potent than fibrillar Aβ at inducing isAPP retention. These results validate the potential of these proteins as therapeutic strategies that prevent the Aβ-induced effects. In hence, given that Aβ decreases the levels of proteins involved in its own clearance, this may contribute to the mechanisms underlying AD pathology.
authors.affiliation: Laboratório de Neurociências, Centro de Biologia Celular, SACS, Universidade de Aveiro, Aveiro, Portugal.
authors.forename: A G
authors.initials: AG
authors.lastname: Henriques
authors.forename: J M
authors.initials: JM
authors.lastname: Oliveira
authors.forename: B
authors.initials: B
authors.lastname: Gomes
authors.forename: R
authors.initials: R
authors.lastname: Ruivo
authors.forename: E F
authors.initials: EF
authors.lastname: da Cruz e Silva
authors.forename: O A B
authors.initials: OA
authors.lastname: da Cruz e Silva
mesh_terms: D000199:Actins / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D018260:Gelsolin / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000199:Actins; D016229:Amyloid beta-Peptides; D018260:Gelsolin; D007797:Laminin