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

Feb 9, 2023Neurobiology of aging

Orexin-A worsens memory problems in Alzheimer's mice by harming brain cell connections and changing amyloid beta processing

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Abstract

Orexin-A (OXA) aggravates memory impairments and circadian rhythm disturbances in 3xTg-AD mice.

OXA is linked to increased amyloid beta (Aβ) levels and tau pathologies in 3xTg-AD mice.
Cognitive deficits are exacerbated by OXA, affecting both memory and synaptic plasticity.
Hippocampal long-term potentiation (LTP) depression is worsened by OXA treatment.
OXA influences the expression of BACE1 and NEP, which are involved in Aβ production and clearance.
Disruption of circadian rhythms and the sleep-wake cycle may underlie the cognitive effects of OXA.

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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 electrophysiological mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid β (Aβ) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, Aβ levels, tau hyperphosphorylation, BACE1 and NEP expression, and circadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased Aβ and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA aggravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing Aβ production and decreasing Aβ clearance through disruption of the circadian rhythm and sleep-wake cycle.

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

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