Institute for Metabolic and Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, China.
Institute for Metabolic and Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, China.
Exp Neurol. 2020 May;327:113249. doi: 10.1016/j.expneurol.2020.113249. Epub 2020 Feb 15.
Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with the etiology on the early stage of Alzheimer's disease (AD). Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of AD. Adiponectin, a peptide hormone secreted by adipocytes, plays a critical role in insulin sensitizing, anti-inflammatory, and anti-diabetic effects in peripheral tissues. We previously showed that AdipoRon, as an agonist of adiponectin, promotes neurite outgrowth under ischemia. However, the role of AdipoRon on neural stem cells (NSCs) proliferation and cognitive dysfunction in the early stage of AD remains unknown. In this study, we investigated the role of AdipoRon on cognitive dysfunction and deficits of NSCs proliferation in AD. The in vivo study showed that AdipoRon improved either cognitive dysfunction or impaired NSCs proliferation in hippocampus DG region in APP/PS1 transgenic (Tg) mice. In addition, AdipoRon treatment also suppressed the β-amyloid (Aβ) deposition and inhibited β-secretase 1(BACE1) expression in both cortex and hippocampus of APP/PS1 Tg mice. The in vitro study further suggested that AdipoRon significantly alleviated Aβ-induced cell viability and neuronal morphology in primary neurons. Both AdipoR1 silencing and compound C, inhibitor of AMPK, completely abolished the effect of AdipoRon. Interestingly, AdipoRon also protected the dissipation of the ΔΨm caused by Aβ toxicity in primary neurons, which was reversed by compound C. In NE-4C NSCs, AdipoRon significantly promoted the Aβ-induced impaired cell proliferation through AdipoR1/AMPK/CREB pathway. Furthermore, inhibition of AMPK by compound C also reversed the promotive effects of AdipoRon on cognition and proliferation of NSCs of APP/PS1 Tg mice, suggesting a AMPK-dependent mechanism by AdipoRon in AD in vivo. Taken together, these results suggested that AdipoRon alleviated the cognitive dysfunction of AD mice, inhibited the Aβ deposition by inhibiting BACE1 expression and promoted the impaired hippocampal NSCs proliferation on the early stage in vivo. The mechanisms involved activation of AdipoR1/AMPK pathway. Therefore, AdipoRon might be a potential candidate for the treatment of AD on the early stage.
海马齿状回（DG）中的成人神经发生与阿尔茨海默病（AD）早期的病因有关。影响成人海马神经发生的因素已被证明有助于 AD 的神经病理学。脂联素是一种由脂肪细胞分泌的肽激素，在周围组织中发挥着胰岛素敏化、抗炎和抗糖尿病的关键作用。我们之前曾表明，AdipoRon 作为脂联素的激动剂，可在缺血下促进神经突生长。然而，AdipoRon 对 AD 早期神经干细胞（NSCs）增殖和认知功能障碍的作用尚不清楚。在这项研究中，我们研究了 AdipoRon 在 AD 中对认知功能障碍和 NSCs 增殖缺陷的作用。体内研究表明，AdipoRon 改善了 APP/PS1 转基因（Tg）小鼠海马 DG 区的认知功能障碍或 NSCs 增殖受损。此外，AdipoRon 治疗还抑制了 APP/PS1 Tg 小鼠皮质和海马中的β-淀粉样蛋白（Aβ）沉积并抑制了β-分泌酶 1（BACE1）的表达。体外研究进一步表明，AdipoRon 可显著减轻 Aβ诱导的原代神经元活力和神经元形态的损伤。AdipoR1 沉默和 AMPK 抑制剂化合物 C 完全消除了 AdipoRon 的作用。有趣的是，AdipoRon 还保护了原代神经元中由 Aβ毒性引起的ΔΨm 耗散，而化合物 C 则逆转了这一作用。在 NE-4C NSCs 中，AdipoRon 显著通过 AdipoR1/AMPK/CREB 通路促进了 Aβ诱导的受损细胞增殖。此外，化合物 C 对 AMPK 的抑制也逆转了 AdipoRon 对 APP/PS1 Tg 小鼠认知和 NSCs 增殖的促进作用，表明 AdipoRon 在体内 AD 中存在一种 AMPK 依赖性机制。总之，这些结果表明，AdipoRon 减轻了 AD 小鼠的认知功能障碍，通过抑制 BACE1 表达抑制了 Aβ沉积，并促进了体内早期海马 NSCs 的受损增殖。涉及激活 AdipoR1/AMPK 通路的机制。因此，AdipoRon 可能是治疗 AD 早期的潜在候选药物。
