Roles of glutamate receptors in a novel in vitro model of early, comorbid cerebrovascular, and Alzheimer's diseases.

Systemic multimorbidity is highly prevalent in the elderly and, remarkably, coexisting neuropathological markers of Alzheimer's (AD) and cerebrovascular (CVD) diseases are found at autopsy in most brains of patients clinically diagnosed as AD. Little is known on neurodegeneration peculiar to comorbidities, especially at early stages when pathogenesis may propagate at subclinical levels. We developed a novel in vitro model of comorbid CVD/AD in organotypic hippocampal cultures, by combining oxygen-glucose deprivation (OGD) and exposure to amyloid-Aβ oligomers (AβOs), both applied at levels subtoxic to neurons when used in isolation. We focused on synaptic proteins and the roles of glutamate receptors, which have been implicated in many basic and clinical approaches to either CVD or AD. Subtoxic insults by OGD and AβOs synergized to reduce levels of synaptophysin (SYP) and PSD-95 without cell death, while effects of antagonists of either metabotropic or ionotropic glutamate receptors were distinct from reports in models of isolated CVD or AD. In particular, modulation of glutamate receptors differentially impacted SYP and PSD-95, and antagonists of a single receptor subtype had distinct effects when either isolated or combined. Our findings highlight the complexity of CVD/AD comorbidity, help understand variable responses to glutamate receptor antagonists in patients diagnosed with AD and may contribute to future development of therapeutics based on investigation of the pattern of progressive comorbidity.