Bone Marrow-Derived Mesenchymal Stem Cells and γ-Secretase Inhibitor Treatments Suppress Amyloid- β 25-35-Induced Cognitive Impairment in Rat Dams and Cortical Degeneration in Offspring

Asmaa Gaber; Ahlam M Elbakry; Rabab M Aljarari; Fatima A Jaber; Yasser A Khadrawy; Dina Sabry; Rasha E Abo-ELeneen; Osama M Ahmed

doi:10.1155/2023/2690949

Bone Marrow-Derived Mesenchymal Stem Cells and γ-Secretase Inhibitor Treatments Suppress Amyloid- β 25-35-Induced Cognitive Impairment in Rat Dams and Cortical Degeneration in Offspring

Stem Cells Int. 2023 May 25:2023:2690949. doi: 10.1155/2023/2690949. eCollection 2023.

Authors

Asmaa Gaber¹, Ahlam M Elbakry¹, Rabab M Aljarari², Fatima A Jaber², Yasser A Khadrawy³, Dina Sabry^{4

5}, Rasha E Abo-ELeneen¹, Osama M Ahmed⁶

Affiliations

¹ Comparative Anatomy and Embryology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni Suef, Egypt.
² Department of Biology, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia.
³ Medical Physiology Department, Medical Branch Department, National Research Center, Giza, Egypt.
⁴ Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Badr University in Cairo, Cairo 11829, Egypt.
⁵ Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt.
⁶ Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni Suef, Egypt.

Abstract

Alzheimer's disease (AD) is the most frequent cause of age-related neurodegeneration and ensuing cognitive impairment. Progressive deposition of extracellular amyloid beta (Aβ) aggregates (plaques) and intracellular hyperphosphorylated Tau protein (p-Tau) are the core pathological markers of AD but may precede clinical symptoms by many years, presenting a therapeutic window of opportunity. Females are more frequently afflicted by AD than males, necessitating evaluation of novel treatments for the female population. The current study examined the protective efficacies of intravenous bone marrow-derived mesenchymal stem cells (BM-MSCs) and oral gamma-secretase inhibitor-953 (GSI-953) during pregnancy on cognitive impairment in rat dams and neurodegeneration in offspring induced by intracerebroventricular injection of Aβ25-35 prior to pregnancy. The Aβ25-35 (AD) group exhibited significant (P < 0.001) impairments in the Y-maze and novel object recognition test performance prior to conception. Histological analysis of the offspring cortex revealed substantial dendritic shrinkage and activation of microglial cells, while neurochemical analysis demonstrated significant increases in the proinflammatory cytokine interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). In contrast, BM-MSC or GSI-953 treatment of dams following Aβ25-35 injection significantly (P < 0.001) reduced the number and size of activated microglial cells, markedly increased dendrite length, and reversed proinflammatory cytokine elevations in offspring. Moreover, BM-MSC or GSI-953 treatment reversed the Aβ25-35-induced amyloid precursor protein and p-Tau elevations in the offspring brain; these changes were accompanied by upregulation of the brain-derived neurotrophic factor and downregulation of glycogen synthase kinase-3β in the serum and brain. Treatment with BM-MSCs or GSI-953 also reversed Aβ25-35-induced elevations in different gene expressions in the neonatal cortex. Finally, treatment of dams with BM-MSCs or GSI-953 prevented the Aβ25-35-induced disruption of newborn brain development. Thus, BM-MSC and GSI-953 treatments have broad-spectrum effects against Aβ25-35-induced brain pathology, including the suppression of neural inflammation, restoration of developmental plasticity, and promotion of neurotrophic signaling.