Background: Prolactin-releasing peptide (PrRP) is a potential drug for the treatment of obesity and associated Type 2 Diabetes Mellitus (T2DM) due to its strong anorexigenic and antidiabetic properties. In our recent study, the lipidized PrRP analog palm11-PrRP31 was proven to exert beneficial effects in APP/PS1 mice, a model of Alzheimer´s Disease (AD)-like amyloid-β (Aβ) pathology, reducing the Aβ plaque load, microgliosis and astrocytosis in the hippocampus and cortex.

Objective: In this study, we focused on the neuroprotective and anti-inflammatory effects of palm11-PrRP31 and its possible impact on synaptogenesis in the cerebellum of APP/PS1 mice, because others have suggested that cerebellar Aβ plaques contribute to cognitive deficits in AD.

Methods: APP/PS1 mice were treated subcutaneously with palm11-PrRP31 for 2 months, then immunoblotting and immunohistochemistry were used to quantify pathological markers connected to AD, compared to control mice.

Results: In the cerebella of 8 months old APP/PS1 mice, we found widespread Aβ plaques surrounded by activated microglia detected by ionized calcium-binding adapter molecule (Iba1), but no increase in astrocytic marker Glial Fibrillary Acidic Protein (GFAP) compared to controls. Interestingly, no difference in both presynaptic markers syntaxin1A and postsynaptic marker spinophilin was registered between APP/PS1 and control mice. Palm11-PrRP31 treatment significantly reduced the Aβ plaque load and microgliosis in the cerebellum. Furthermore, palm11-PrRP31 increased synaptogenesis and attenuated neuroinflammation and apoptosis in the hippocampus of APP/PS1 mice.

Conclusion: These results suggest palm11-PrRP31 is a promising agent for the treatment of neurodegenerative disorders.

背景：催乳素释放肽 (PrRP) 是一种潜在的治疗肥胖症和相关 2 型糖尿病 (T2DM) 的药物，因为它具有很强的厌食和抗糖尿病特性。在我们最近的研究中，脂质化 PrRP 类似物 palm11-PrRP31 被证明对 APP/PS1 小鼠产生有益作用，这是一种阿尔茨海默病 (AD) 样淀粉样蛋白-β (Aβ) 病理学模型，可减少 Aβ 斑块负荷，海马和皮层的小胶质细胞增生和星形胶质细胞增生。

目的：在这项研究中，我们专注于 palm11-PrRP31 的神经保护和抗炎作用及其对 APP/PS1 小鼠小脑突触发生的可能影响，因为其他人认为小脑 Aβ 斑块会导致 AD 认知缺陷。

方法：与对照小鼠相比，APP/PS1 小鼠用 palm11-PrRP31 皮下治疗 2 个月，然后使用免疫印迹和免疫组织化学来量化与 AD 相关的病理标志物。

结果：在 8 个月大的 APP/PS1 小鼠的小脑中，我们发现由离子化钙结合衔接分子 (Iba1) 检测到的被活化小胶质细胞包围的广泛 Aβ 斑块，但与星形胶质细胞标志物胶质纤维酸性蛋白 (GFAP) 相比没有增加控制。有趣的是，在 APP/PS1 和对照小鼠之间，突触前标志物 syntaxin1A 和突触后标志物 spinophilin 没有差异。Palm11-PrRP31 治疗显着降低了小脑中的 Aβ 斑块负荷和小胶质细胞增生。此外，palm11-PrRP31 增加突触发生并减轻 APP/PS1 小鼠海马的神经炎症和细胞凋亡。

结论：这些结果表明 palm11-PrRP31 是一种有前途的治疗神经退行性疾病的药物。