Orexin-A aggravates cognitive deficits in 3xTg-AD mice by exacerbating synaptic plasticity impairment and affecting amyloid ,B metabolism

Dementia is the main clinical feature of Alzheimer's disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APP/PS1 mice. However, the effects of OXA on other types of cognitive deficits, especially in 3xTg-AD mice exhibiting both plaque and tangle pathologies, have not been reported. Furthermore, the potential electrophysiolog-ical mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid ,B (A,B) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, A,B levels, tau hyperphosphorylation, BACE1 and NEP expression, and cir-cadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased A,B and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA ag-gravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing A,B production and decreasing A,B clearance through disruption of the circadian rhythm and sleep-wake cycle.(c) 2023 Elsevier Inc. All rights reserved.