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Purpose Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD). As vascular endothelial growth factor (VEGF) has been shown to be protective in AD, the aim of this study was to investigate the effects of VEGF on mitochondrial function in models of AD. Materials and methods Adeno associated virus (AAV)-VEGF was injected into the hippocampus of APP/PS1 mice. Cognitive function was assessed in these mice with use of the Morris water maze (MWM) and β-amyloid (Aβ) levels in the hippocampus were also measured. Cell viability and reactive oxygen species (ROS) levels were determined in the SH-SY5Y cells treated with Aβ25-35 which served as a cell model of AD. Transmission electron microscopy (TEM) was used to evaluate structural changes in mitochondria and mitochondrial DNA (mtDNA) copy number and mitochondrial membrane potential (MMP) were also recorded. Finally, we investigated the effects of VEGF upon mitochondrial biogenesis, autophagy and mitochondrial autophagy (mitophagy) as determined both in vivo and in vitro with western blots. Results VEGF treated mice showed improvements in spatial learning and memory along with reduced Aβ levels. VEGF protected SH-SY5Y cells against Aβ25-35 induced neurotoxicity as demonstrated by increased cell viability and decreased ROS production. Associated with these effects were improvements in mitochondrial structure and function, and increased numbers of mitochondria resulting from stimulation of mitochondrial biogenesis. Conclusions VEGF alleviates Aβ related patholoy in models of AD. In part, these beneficial effects of VEGF result from protection of mitochondria and stimulation of mitochondrial biogenesis.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease and mitochondrial impairment is a key feature of AD. The mitochondrial DNA (mtDNA) epigenetic mechanism is a relatively new field compared to nuclear DNA. The relationship between mtDNA epigenetic mechanism and AD hasn’t been established. So we analyzed the mtDNA methylation in D-loop region and 12 S rRNA gene in the hippocampi in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice by bisulfite pyrosequencing. Mitochondrial DNA copy number and gene expression were studied by quantitative real-time PCR (qRT-PCR). We observed a decrease in the displacement loop (D-loop) methylation and an increase in 12 S rRNA gene methylation, while both the mtDNA copy number and the mitochondrial gene expression were reduced in APP/PS1 transgenic mice. In summary, the present finding suggest that mtDNA methylation may play a role in AD pathology, which warrants larger future investigations.

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease, but the pathogenesis is unclear. Damaged mitochondrial biogenesis has been observed in AD. Increasing evidence suggests that mitochondrial biogenesis is involved in the pathogenesis of AD, but the exact mechanism is unclear. In this study, we used the amyloid precursor protein Swedish mutations K594N/M595L (APPswe)/presenilin 1 with the exon-9 deletion (PS1dE9) transgenic mouse model of AD, which was successfully established by the expression of amyloid β precursor protein and presenilin 1 (PS1). Then, we compared APPswe/PS1dE9 transgenic mice with and without melatonin (MT) in drinking water for 4 months (estimated 0.5 mg/day) and control C57BL/6J mice without MT for expression of mitochondrial biogenesis factors (mitochondrial transcription factor A, nuclear respiratory factor 1 and 2, peroxisome proliferator-activated receptor γ coactivator 1-α), mitochondrial structure, mitochondrial DNA to nuclear DNA ratio, behavioral changes, and amyloid β (Aβ) deposition and soluble Aβ levels in the cerebral cortex and hippocampus. Compared with controls, APPswe/PS1dE9 mice with long-term MT intake showed increased levels of mitochondrial biogenesis factors, alleviated mitochondrial impairment, enhanced mitochondrial DNA copy number, improved spatial learning and memory deficits, and reduced Aβ deposition and soluble Aβ levels. Defective mitochondrial biogenesis may contribute toward the damaged mitochondrial structure and function in AD. MT may alleviate AD by promoting mitochondrial biogenesis.

Alzheimer disease (AD) is the most common form of dementia. Amyloid β-peptide (Aβ) deposition is a major neuropathologic feature of AD. When unfolded or misfolded proteins accumulate in mitochondria, the unfolded protein responses (UPRmt) is initiated. Numerous lines of evidence show that AD pathogenesis involves mitochondrial dysfunction. However little is known about whether the UPRmt is engaged in the process of AD development. In this study, we investigated the UPRmt in mouse and cell models of AD. We found that UPRmt was activated in the brain of 3 and 9 months old APP/PS1 mice, and in the SHSY5Y cells after exposure to Aβ25–35, Aβ25–35 triggered UPRmt in SHSY5Y cells could be attenuated upon administration of simvastatin or siRNA for HMGCS-1 to inhibit the mevalonate pathway, and or upon knocking down Serine palmitoyltransferase long chain subunit 1 (SPTLC-1) to lower sphingolipid biosynthesis. We observed that inhibition of UPRmt aggravated cytotoxic effects of Aβ25–35 in SHSY5Y cells. Our research suggests that the UPRmt activation and two pathways necessary for this response, and further provides evidence for the cytoprotective effect of UPRmt during the AD process.

Background: Alzheimer’s disease (AD) is one of the common neurodegenerative diseases and is characterized by the accumulation of amyloid-β (Aβ). Orexin-A is a neuropeptide produced in the hypothalamus and thought to be involved in the pathogenesis of AD. However, its underlying mechanism and signaling pathway remains unclear. The aim of this work was to investigate the effect of Orexin-A on AD, and to explore its potential mechanism and signaling pathway. Methods: SH-SY5Y cells that were stably transfected with the Swedish mutant amyloid precursor protein (APPswe), a cell model of AD with excessive Aβ production, were used in this study. Cells were treated with Orexin-A, and with or without SB203580, an inhibitor of the p38 mitogen-activated protein kinase (MAPK) pathway, one of the key MAPK pathways associated with cell death. Following treatment, cells were collected and analyzed by western blotting, ELISA, electron microscopy, real-time PCR, fluorescence microscopy, and other biochemical assays. Results: Orexin-A increased the level of Aβ 1–40 and Aβ 1–42 in the cell medium, and activated the p38 MAPK pathway. As evidenced by the CCK-8 and ELISA BrdU assays, Orexin-A decreased cell viability and cell proliferation. Electron microscopic analysis used to observe the morphology of mitochondria, showed that Orexin-A increased the percentage of abnormal mitochondria. Further, decreased activity of cytochrome c oxidase (CCO), level of ATP, and mitochondrial DNA (mtDNA) copy number following Orexin-A treatment showed that Orexin-A exacerbated mitochondrial dysfunction. The level of intracellular reactive oxygen species (ROS), which is mainly generated in mitochondria and reflects mitochondrial dysfunction, was also increased by Orexin-A. SB203580 blocked the cytotoxicity and mitochondrial impairment aggravated by Orexin-A. Conclusions: These findings demonstrate that Orexin-A aggravates cytotoxicity and mitochondrial impairment in SH-SY5Y cells transfected with APPswe through the p38 MAPK pathway, and suggest that Orexin-A participates in the pathogenesis of AD, which may provide a new treatment target in the future.