Gaber Asmaa, Ahmed Osama M, Khadrawy Yasser A, Zoheir Khairy M A, Abo-ELeneen Rasha E, Alblihed Mohamed A, Elbakry Ahlam M
Comparative Anatomy and Embryology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef P.O. Box 62521, Egypt.
Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef P.O. Box 62521, Egypt.
Biology (Basel). 2023 Jun 25;12(7):905. doi: 10.3390/biology12070905.
Alzheimer's disease (AD) is the most common cause of age-related neurodegeneration and cognitive decline. AD more commonly occurs in females than in males, so it is necessary to consider new treatments specifically targeting this population. The present study investigated the protective effects of Begacestat (γ-secretase inhibitor-953, GSI-953) and bone marrow-derived mesenchymal stem cells (BM-MSCs) during pregnancy on cognitive impairment in rat dams and neurodegeneration in offspring caused by the intracerebroventricular injection of Aβ 25-35 before pregnancy. The performances of dams injected with amyloid-β 25-35 (Aβ 25-35) during behavioral tests were significantly impaired. The offspring of Aβ 25-35-injected dams treated with BM-MSCs or GSI-953 showed a dramatically reduced number and size of activated microglial cells, enhancement in the processes length, and a decrease in the proinflammatory cytokine levels. Additionally, BM-MSC or GSI-953 therapy reduced Aβ 25-35-induced increases in tau phosphorylation and amyloid precursor protein levels in the neonates' hippocampus and elevated the lower levels of glycogen synthase kinase-3 and brain-derived neurotrophic factor; moreover, reversed Aβ 25-35-induced alterations in gene expression in the neonatal hippocampus. Finally, the treatments with BM-MSC or GSI-953 are globally beneficial against Aβ 25-35-induced brain alterations, particularly by suppressing neural inflammation, inhibiting microglial cell activation, restoring developmental plasticity, and increasing neurotrophic signaling.
阿尔茨海默病（AD）是与年龄相关的神经退行性变和认知衰退的最常见原因。AD在女性中比在男性中更常见，因此有必要考虑专门针对这一人群的新治疗方法。本研究调查了孕期使用贝加西他（γ-分泌酶抑制剂-953，GSI-953）和骨髓间充质干细胞（BM-MSCs）对妊娠大鼠因在怀孕前脑室内注射Aβ 25-35所致认知障碍及子代神经退行性变的保护作用。在行为测试中，注射淀粉样β 25-35（Aβ 25-35）的母鼠表现明显受损。用BM-MSCs或GSI-953治疗Aβ 25-35注射母鼠的子代，活化小胶质细胞的数量和大小显著减少，突起长度增加，促炎细胞因子水平降低。此外，BM-MSC或GSI-953治疗降低了Aβ 25-35诱导的新生鼠海马体中tau蛋白磷酸化和淀粉样前体蛋白水平的升高，并提高了糖原合酶激酶-3和脑源性神经营养因子的较低水平；此外，还逆转了Aβ 25-35诱导的新生鼠海马体基因表达改变。最后，BM-MSC或GSI-953治疗对Aβ 25-35诱导的脑改变具有全面的有益作用，特别是通过抑制神经炎症、抑制小胶质细胞活化、恢复发育可塑性和增加神经营养信号传导。
