Compensatory enhancement of orexinergic system functionality induced by amyloid-β protein: a neuroprotective response in Alzheimer's disease.

BACKGROUND

Amyloid-β protein (Aβ) accumulation is a defining characteristic of Alzheimer's disease (AD), resulting in neurodegeneration and a decline in cognitive function. Given orexin's well-documented role in enhancing memory and cognition, this study investigates its potential to regulate Aβ-induced neurotoxicity, offering new perspectives into AD management.

METHODS

This paper simulated Aβ accumulation in the hippocampus of AD patients by administering Aβ oligomers into the bilateral hippocampal dentate gyrus of ICR mice. Inflammatory cytokines (IL-6, TNF-α) and orexin-A levels were measured by ELISA. Additionally, the excitability of orexinergic neurons was assessed by IHC targeting c-Fos expression. These methodologies evaluated the Aβ-induced neuroinflammation, orexinergic system functionality, and dexamethasone's (Dex) effects on these processes.

RESULTS

Injection of Aβ oligomer resulted in elevated levels of IL-6, TNF-α, and orexin-A in the hippocampus, as well as increased excitability of orexinergic neurons in the lateral hypothalamus (LH). Dex treatment reduced neuroinflammation, causing a reduction in orexin-A levels and the excitability of orexinergic neurons.

CONCLUSION

Aβ-induced neuroinflammation is accompanied by enhanced levels of orexin-A and orexinergic neuron excitability. These findings suggest that the enhanced functionality of the orexinergic system may become a compensatory neuroprotective mechanism to counteract neuroinflammation and enhance cognitive function.