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

• Published in: Neurobiology of aging Vol. 124; pp. 71 - 84
• Main Authors: Li, Yi-Ying, Yu, Kai-Yue, Cui, Yu-Jia, Wang, Zhao-Jun, Cai, Hong-Yan, Cao, Ji-Min, Wu, Mei-Na
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2023
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - metabolism; Animals; Aspartic Acid Endopeptidases - metabolism; Cognition; Disease Models, Animal; Long-term potentiation; Memory Disorders - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuronal Plasticity; Orexin-A; Orexins; Tau phosphorylation; tau Proteins; β-amyloid protein; Tau phosphorylation; β-amyloid protein; Cognition; Alzheimer's disease; Orexin-A; Long-term potentiation
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2023.01.008

•Exogenous orexin-A (OXA) aggravated cognitive deficits and LTP depression in 3xTg-AD mice.•OXA increased Aβ and tau pathologies in the brain in 3xTg-AD mice.•OXA increased Aβ levels by affecting the expression of BACE1 and NEP.•OXA aggravated the disturbance of the circadian locomotor rhythm in 3xTg-AD mice. 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.