title: Effect of α-synuclein on amyloid β-induced toxicity: relevance to Lewy body variant of Alzheimer disease.
abstract: Alzheimer's disease, the most prevalent age-related neurodegenerative disease, is characterized by the presence of extracellular senile plaques composed of amyloid-beta (Aβ) peptide and intracellular neurofibrillary tangles. More than 50 % of Alzheimer's disease (AD) patients also exhibit abundant accumulation of α-synuclein (α-Syn)-positive Lewy bodies. This Lewy body variant of AD (LBV-AD) is associated with accelerated cognitive dysfunction and progresses more rapidly than pure AD. In addition, it has been suggested that Aβ and α-Syn can directly interact. In this study we investigated the effect of α-Syn on Aβ-induced toxicity in cortical neurons. In order to mimic the intracellular accumulation of α-Syn observed in the brain of LBV-AD patients, we used valproic acid (VPA) to increase its endogenous expression levels. The release of α-Syn from damaged presynaptic terminals that occurs during the course of the disease was simulated by challenging cells with recombinant α-Syn. Our results showed that either VPA-induced α-Syn upregulation or addition of recombinant α-Syn protect primary cortical neurons from soluble Aβ1-42 decreasing the caspase-3-mediated cell death. It was also found that neuroprotection against Aβ-induced toxicity mediated by α-Syn overexpression involves the PI3K/Akt cell survival pathway. Furthermore, recombinant α-Syn was shown to directly interact with Aβ1-42 and to decrease the levels of Aβ1-42 oligomers, which might explain its neuroprotective effect. In conclusion, we demonstrate that either endogenous or exogenous α-Syn can be neuroprotective against Aβ-induced cell death, suggesting a cell defence mechanism during the initial stages of the mixed pathology.
authors: Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal. rositaresende@gmail.com
authors: Rosa
authors: R
authors: Resende
authors: Sueli C F
authors: SC
authors: Marques
authors: Elisabete
authors: E
authors: Ferreiro
authors: Isaura
authors: I
authors: Simões
authors: Catarina R
authors: CR
authors: Oliveira
authors: Cláudia M F
authors: CM
authors: Pereira
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D014635:Valproic Acid / Q000494:pharmacology; D051844:alpha-Synuclein / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); D014635:Valproic Acid; D053148:Caspase 3
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