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BACKGROUND We observed the effects of nuclear factor E2-related factor 2 (Nrf2) downregulation via intrahippocampal injection of a lentiviral vector on cognition in senescence-accelerated mouse prone 8 (SAMP8) to investigate the role of the (Nrf2)/antioxidant response element (ARE) pathway in age-related changes. MATERIAL AND METHODS Control lentivirus and Nrf2-shRNA-lentivirus were separately injected into the hippocampus of 4-month-old SAMR1 and SAMP8 mice and then successfully downregulated Nrf2 expression in this brain region. Five months later, cognitive function tests, including the novel object test, the Morris water maze test, and the passive avoidance task were conducted. Glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1) immunohistochemistry was performed to observe an inflammatory response. Presynaptic synapsin (SYN) were observed by immunofluorescence. We then determined the Nrf2-regulated, heme oxygenase-1 (HO-1), P65, postsynaptic density protein (PSD), and SYN protein levels. The ultrastructure of neurons and synapses in the hippocampal CA1 region was observed by transmission electron microscopy. RESULTS Aging led to a decline in cognitive function compared with SAMR1 mice and the Nrf2-shRNA-lentivirus further exacerbated the cognitive impairment in SAMP8 mice. Nrf2, HO-1, PSD, and SYN levels were significantly reduced (all P&lt;0.05) but high levels of inflammation were detected in SAMP8 mice with low expression of Nrf2. Furthermore, neurons were vacuolated, the number of organelles decreased, and the number of synapses decreased. CONCLUSIONS Downregulation of Nrf2 suppressed the Nrf2/ARE pathway, activated oxidative stress and neuroinflammation, and accelerated cognitive impairment in SAMP8 mice. Downregulation of Nrf2 accelerates the aging process through neuroinflammation and synaptic plasticity.

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Downregulated Nuclear Factor E2-Related Factor 2 (Nrf2) Aggravates Cognitive Impairments via Neuroinflammation and Synaptic Plasticity in the Senescence-Accelerated Mouse Prone 8 (SAMP8) Mouse: A Model of Accelerated Senescence