Excessive mitochondrial fission is a prominent early event and contributes to mitochondrial dysfunction, synaptic failure, and neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. To determine whether dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fragmentation, can be a disease-modifying therapeutic target for AD, we examined the effects of Drp1 inhibitor on mitochondrial and synaptic dysfunctions induced by oligomeric amyloid-β (Aβ) in neurons and neuropathology and cognitive functions in Aβ precursor protein/presenilin 1 double-transgenic AD mice. Inhibition of Drp1 alleviates mitochondrial fragmentation, loss of mitochondrial membrane potential, reactive oxygen species production, ATP reduction, and synaptic depression in Aβ-treated neurons. Furthermore, Drp1 inhibition significantly improves learning and memory and prevents mitochondrial fragmentation, lipid peroxidation, BACE1 expression, and Aβ deposition in the brain in the AD model. These results provide evidence that Drp1 plays an important role in Aβ-mediated and AD-related neuropathology and in cognitive decline in an AD animal model. Therefore, inhibiting excessive Drp1-mediated mitochondrial fission may be an efficient therapeutic avenue for AD. Mitochondrial fission relies on the evolutionary conserved dynamin-related protein 1 (Drp1). Drp1 activity and mitochondria fragmentation are significantly elevated in the brains of sporadic Alzheimer's disease (AD) cases. In the present study, we first demonstrated that the inhibition of Drp1 restored amyloid-β (Aβ)-mediated mitochondrial dysfunctions and synaptic depression in neurons and significantly reduced lipid peroxidation, BACE1 expression, and Aβ deposition in the brain of AD mice. As a result, memory deficits in AD mice were rescued by Drp1 inhibition. These results suggest that neuropathology and combined cognitive decline can be attributed to hyperactivation of Drp1 in the pathogenesis of AD. Therefore, inhibitors of excessive mitochondrial fission, such as Drp1 inhibitors, may be a new strategy for AD.

BACE1 is the rate-limiting enzyme for amyloid-β peptides (Aβ) generation, a key event in the pathogenesis of Alzheimer's disease (AD). By an unknown mechanism, levels of BACE1 and a BACE1 mRNA-stabilizing antisense RNA (BACE1-AS) are elevated in the brains of AD patients, implicating that dysregulation of BACE1 expression plays an important role in AD pathogenesis. We found that nuclear factor erythroid-derived 2-related factor 2 (NRF2/ NFE2L2) represses the expression of BACE1 and BACE1-AS through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of BACE1 and BACE1-AS expression is independent of redox regulation. NRF2 activation decreases production of BACE1 and BACE1-AS transcripts and Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.A lzheimer's disease (AD) is the most common type of dementia and is characterized by accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. BACE1 is the only β-secretase responsible for the production of Aβ and therefore plays a key role in the pathogenesis of AD (1-3). A long noncoding RNA transcribed from the opposite strand of BACE1 (BACE1-AS) stabilizes BACE1 mRNA by forming a heteromeric RNA duplex (4). BACE1 mRNA and protein levels as well as BACE1-AS transcript are abnormally elevated in postmortem brain tissue from patients with AD (4-8). A small increase in BACE1 induces a dramatic increase in Aβ production (9), and inhibitors of BACE1 enzyme activity are being pursued as a therapeutic strategy for AD (10). Genetic reduction of BACE1 or BACE1-AS levels reduces Aβ plaque pathology in mouse models of AD (4, 11-13), suggesting that identification of transcriptional repressors of BACE1 gene expression could provide an avenue for intervention in AD.Nuclear factor erythroid-derived 2-related factor 2 (NRF2/ NFE2L2) is a transcription factor that binds to the antioxidant response elements (AREs) and regulates a variety of cytoprotective and detoxification genes (14). In the inactive state, kelch-like ECHassociated protein1 (KEAP1) binds to NRF2 and retains it in the cytoplasm where it is degraded by proteasomes (15, 16). NRF2 activators, such as sulforaphane and tert-butylhydroquinone (tBHQ), modify cysteine residues of KEAP1, leading to conformational change and disrupting the KEAP1-NRF2 interaction, and accumulated NRF2 then translocates to the nucleus and transactivates target genes by binding to their AREs (17,18). NRF2 levels are reduced, and NRF2 is localized predominately in the cytoplasm of hippocampal neurons of AD patients (19). In addition, altered expression of NRF2 target genes is associated with Aβ pathology in AD animal models (20)(21)(22). Here we show that NRF2 is a negative regulator of BACE1 expression that can am...

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Ischemic stroke is a leading cause of morbidity and death, with the outcome largely determined by the amount of hypoxia-related neuronal death in the affected brain regions. Cerebral ischemia and hypoxia activate the Notch1 signaling pathway and four prominent interacting pathways (NF-κB, p53, HIF-1α and Pin1) that converge on a conserved DNA-associated nuclear multi-protein complex, which controls the expression of genes that can determine the fate of neurons. When neurons experience a moderate level of ischemic insult, the nuclear multiprotein complex up-regulates adaptive stress response genes encoding proteins that promote neuronal survival, but when ischemia is more severe the nuclear multi-protein complex induces genes encoding proteins that trigger and execute a neuronal death program. We propose that the nuclear multi-protein transcriptional complex is a molecular mediator of neuronal hormesis and a target for therapeutic intervention in stroke.