Affiliations: [a] Departamento de Investigación Básica, Dirección de Investigación, Instituto de Geriatría, Institutos Nacionales de Salud, Secretaría de Salud, México D.F, México | [b] Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México D.F, México | [c] División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F, México
Correspondence:
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Correspondence to: Clorinda Arias, Departamento de Medicina Genómica y Toxicología Ambiental. Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México. AP 70-228, 04510 México, DF, México. Tel.: +52 55 56229215; Fax: +52 55 56229182; E-mail: [email protected].
Abstract: Synapse loss is considered to be the best correlate of cognitive impairments in Alzheimer's disease (AD), and growing evidence supports the notion that certain events that trigger neuronal death in AD can be initiated by the local activation of caspases within the synaptic compartment. We have demonstrated previously that presynaptic terminals are particularly vulnerable to endoplasmic-reticulum (ER)-stress depending of amyloid-β protein (Aβ). This toxicity included a notable reduction of actin and synaptophysin protein and mitochondrial dysfunction. This synaptic damage was prevented by incubation with a wide range of caspase inhibitor, suggesting the activation of local synaptic apoptotic mechanisms. The ER-resident caspase-12 was initially identified as a mediator of Aβ neurotoxicity. Thus, the current study was conducted to explore the presence and local activation of the caspase-12 in cortical and hippocampal synaptosomes isolated from rat and from the triple transgenic mouse model of AD (3xTg-AD) in the presence of Aβ and ryanodine. Under these conditions, we found mitochondrial failure accompanied by a reduction in actin levels which was dependent on caspase-12 activation suggesting its participation in Aβ-induced synaptic toxicity.
