Mesenchymal Stem Cells and Begacestat Mitigate Amyloid-β 25–35-Induced Cognitive Decline in Rat Dams and Hippocampal Deteriorations in Offspring

SIMPLE SUMMARY: Alzheimer’s is a type of dementia that affects memory, thinking, and behavior. It is a chronic neurological illness. Alzheimer’s disease is the primary cause of dementia in senior individuals and the sixth greatest cause of death in the world. Although several medications are used to treat Alzheimer’s disease, none of them actually prevent the illness from progressing. The groundbreaking finding of stem cells has given rise to fresh optimism for the creation of Alzheimer’s disease-modifying therapies. The therapeutic use of secretase inhibitor (Begacestat) for the treatment of Alzheimer’s disease significantly lowers the amounts of amyloid proteins. The current study focuses on how secretase inhibitor and mesenchymal stem cells are used to treat Alzheimer’s disease in pregnant female rats and how this affects the development of the progeny. According to current research, mesenchymal stem cells or γ-secretase inhibitors treatment against single amyloid protein 25–35 injection for dams repaired histopathological changes, inhibited microglial cell activity, improved behavioral impairments, reduced neuroinflammatory cytokines, and decreased the protein concentration of p-tau and the amyloid precursor protein by increasing the activity of the brain-derived neurotrophic factor, decreasing the expression of NF-κB. Therefore, this study proved a possible protection against Alzheimer’s disease by mesenchymal stem cells and γ-secretase inhibitor. ABSTRACT: 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.