Intrahippocampal injection of Aβ1-42 inhibits neurogenesis and down-regulates IFN-γ and NF-κB expression in hippocampus of adult mouse brain

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by accumulation of amyloid plaques and neurofibrillary tangles. Amyloid-β (Aβ) is widely recognized as a key factor in the pathogenesis of AD. Aβ1-42, a major component of amyloid plaques, has shown synaptotoxicity associated with impaired long-term potentiation and cognitive deficits. Alteration of neurogenesis in AD patients has been reported, while little is known about how Aβ1-42 affects hippocampal neurogenesis in the adult brain. In this study, we injected human Aβ1-42 peptide into hippocampal CA1 area of adult mouse brain bilaterally and evaluated histological change and neurogenesis in the hippocampus. Hematoxylin and eosin (HE) stain showed that Aβ1-42-injection resulted in an extensive neurodegeneration in the Aβ-accumulated area and CA3 in hippocampus. Immunostaining showed that intrahippocampal Aβ1-42-injection dramatically decreased the number of bromodeoxyuridine (BrdU)-positive cells in the dentate gyrus (DG) compared to the vehicle injection. Moreover, a significant decrease in the number of BrdU/double-cortin double-positive cells in Aβ1-42-injected hippocampus was observed, suggesting that Aβ1-42-injection inhibited progenitor cell proliferation and neurogenesis in subgranular zone of the DG in the adult brain. We also found that the Aβ1-42-mediated decline of neurogenesis was associated with decreased protein levels of cytokines interferon-γ (IFN-γ) and transcription factor nuclear factor-kappa B (NF-κB) in the hippocampus. These results suggest that Aβ1-42 inhibits hippocampal neurogenesis in the adult brain possibly through down-regulation of INF-γ and NF-κB signaling pathway. This study provides a new insight into Aβ1-42-mediated decrease in hippocampal neurogenesis in the adult central nervous system.Abbreviations: Aβ, Amyloid-β; AD, Alzheimer’s disease; AβPP (APP), Amyloid β precursor protein; BrdU, Bromodeoxyuridine; CNS, central nervous system; DCX, doublecortin; DG, dentate gyrus; IFN-γ, interferon-γ; NF-κB, nuclear factor-kappa B; NS, normal saline; RT, room temperature; SGZ, subgranular zone; SVZ, subventricular zone.