A long-term high-fat diet influences brain damage and is linked to the activation of HIF-1α/AMPK/mTOR/p70S6K signalling.

High-fat diets (HFDs) are related to the incidence of obesity and diabetes, but the effect of high-fat diet-induced brain damage remains to be clarified. In our study, we found that 24 weeks of a HFD effectively induced obesity and a change in fur color in mice. In addition, the mice also exhibited deficits in learning and memory. We further found that autophagic flux was impaired in mice after HFD feeding. Hypoxia-inducible factor 1α (HIF-1α) expression was significantly increased in HFD-fed mice, and HFD feeding inhibited adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and induced mechanistic target of rapamycin (mTOR) phosphorylation and p70S6K expression. Treatment of HFD-induced BV2 cell model with palmitic acid (PA) was used to further verify a similar result. We concluded that improving tissue hypoxia or enhancing autophagy through the AMPK/mTOR/p70S6K pathway may be a relevant strategy for improving obesity- and ageing-related disorders.

Role of Hypoxia Inducible Factor-1α in Alzheimer's Disease.

Amyloid-ß (Aß) peptides and hyperphosphorylated tau protein are the most important pathological markers of Alzheimer's disease (AD). Neuroinflammation and oxidative stress are also involved in the development and pathological mechanism of AD. Hypoxia inducible factor-1α (HIF-1α) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. Emerging evidence has revealed HIF-1α as a potential medicinal target for neurodegenerative diseases. On the one hand, HIF-1α increases AßPP processing and Aß generation by promoting ß/γ-secretases and suppressing α-secretases, inactivates microglia and reduces their activity, contributes to microglia death and neuroinflammation, which promotes AD pathogenesis. On the other hand, HIF-1α could resist the toxic effect of Aß, inhibits tau hyperphosphorylation and promotes microglial activation. In summary, this review focuses on the potential complex roles and the future perspectives of HIF-1α in AD, in order to provide references for seeking new drug targets and treatment methods for AD.

Ameliorating Ribosylation-Induced Amyloid-ß Pathology by Berberine via Inhibiting mTOR/p70S6K Signaling.

BACKGROUND: Berberine (BBR) plays a neuroprotective role in the pathogenesis of Alzheimer's disease (AD), inhibiting amyloid-ß (Aß) production and promoting Aß clearance. Advanced glycation end products (AGEs) promote Aß aggregation and tau hyperphosphorylation. The activation of mTOR signaling occurring at the early stage of AD has a prominent impact on the Aß production. This work focused on whether BBR regulates the production and clearance of ribosylation-induced Aß pathology via inhibiting mTOR signaling. OBJECTIVE: To explore whether BBR ameliorates ribosylation-induced Aß pathology in APP/PS1 mice. METHODS: Western blot and immunofluorescence staining were used to detect the related proteins of the mammalian target of Rapamycin (mTOR) signaling pathway and autophagy, as well as the related kinases of Aß generation and clearance. Tissue sections and Immunofluorescence staining were used to observe Aß42 in APP/PS1 mice hippocampal. Morris water maze test was used to measure the spatial learning and memory of APP/PS1 mice. RESULTS: BBR improves spatial learning and memory of APP/PS1 mice. BBR limits the activation of mTOR/p70S6K signaling pathway and enhances autophagy process. BBR reduces the activity of BACE1 and γ-secretase induced by D-ribose, and enhances Aß-degrading enzymes and Neprilysin, and inhibits the expression of Aß in APP/PS1 mice. CONCLUSION: BBR ameliorates ribosylation-induced Aß pathology via inhibiting mTOR/p70S6K signaling and improves spatial learning and memory of the APP/PS1 mice.

Metabolic Alterations in the Outer Membrane Vesicles of Patients with Alzheimer's Disease: An LC-MS/MS-based Metabolomics Analysis.

OBJECTIVE: To characterize the specific metabolomics profiles in the outer membrane vesicles (OMVs) of patients with Alzheimer's Disease (AD) and to explore potential metabolic biomarkers and their diagnostic roles. METHODS: Nine AD patients and age- and sex-matched healthy controls were enrolled, and feces were collected. OMVs were extracted, purified, and then analyzed using liquid chromatography-tandem mass chromatography (LC-MS/MS) method coupled with a series of multivariate statistical analyses. RESULTS: Remarkable differences were found between the OMVs from AD patients and those from healthy controls. A number of differential metabolites and several top-altered metabolic pathways were identified. The levels of aspartate, L-aspartate, imidazole-4-acetate and L-glutamate were confirmed to be highly upregulated in AD-OMVs. Other differential metabolites, such as arachidic acid, prostaglandin G2, and leukotriene B4, were also identified. Furthermore, the differential metabolites possessed higher areas under the ROC curve (AUCs). CONCLUSION: Metabolic activity is significantly altered in the OMVs from AD patients. This data might be helpful for identifying novel biomarkers and their diagnostic roles in AD. Furthermore, OMVs metabolomics analysis combined with GWAS could enrich our understanding of the genetic spectrum of AD and lead to early predictions and diagnosis and clinical applications of better AD treatments.

Decrease in Serum Levels of Adiponectin and Increase in 8-OHdG: a Culprit for Cognitive Impairment in the Elderly Patients with Type 2 Diabetes.

BACKGROUND: Adiponectin and 8-Hydroxy-2'-deoxyguanosine (8-OHdG) are identified as important biomarkers in the pathogenesis process of type 2 diabetes mellitus (T2DM). Whether adiponectin and 8-OHdG have a relation to cognitive decline in the elderly T2DM patients has been poorly understood. The aim of this study was to evaluate the effects of adiponectin and 8-OHdG in the elderly patients with T2DM and to determine the role of adiponectin and 8-OHdG in the cognitive impairment of the elderly patients with T2DM. METHODS: 57 individuals were recruited and analyzed , with 26 cases of T2DM without cognitive impairment and 31 cases of T2DM with cognitive impairment. All of them underwent an examination of diabetes scales and blood glucose at different times. A primary diagnosis of diabetes was in line with the diagnosis criteria set by the American Diabetes Association (ADA). Statistical significance was defined as a P-value of less than 0.05. RESULTS: The variables of sex, age, body mass index (BMI), hypertension, diabetes, metabolic syndrome, lacunar cerebral infarction, smoking and drinking in T2DM patients without cognitive impairment and with cognitive impairment showed no difference according to the univariate analysis exploring each variable separately (p>0.05). A significant difference was observed in the serum levels of adiponectin and 8-OHdG and the scales of MMSE and MoCA (p<0.05). Therefore, it was inferred that there is no correlation between glucose metabolic value and cognitive outcome of T2DM patients. Serum levels of adiponectin and 8-OHdG could act as biomarkers of cognitive impairment degree in the elderly T2DM patients. CONCLUSION: Serum levels of adiponectin and 8-OHdG could act as specific and sensitive biomarkers for the early diagnosis and treatment of cognitive impairment in elderly T2DM patients. Serum levels of adiponectin and 8-OHdG have a close relation to the neurological cognitive outcome of the elderly T2DM patients.

Berberine Alleviates Amyloid-beta Pathogenesis Via Activating LKB1/AMPK Signaling in the Brain of APP/PS1 Transgenic Mice.

BACKGROUND: Liver kinase B1 (LKB1)/5'-adenosine monophosphate-activated protein kinase (AMPK) signaling, a metabolic checkpoint, plays a neuro-protective role in the pathogenesis of Alzheimer's disease (AD). Amyloid-ß (Aß) acts as a classical biomarker of AD. The aim of the present study was to explore whether berberine (BBR) activates LKB1/AMPK signaling and ameliorates Aß pathology. METHODS: The Aß levels were detected using enzyme-linked immunosorbent assay and immunohistochemistry. The following biomarkers were measured by Western blotting: phosphorylated (p-) LKB1 (Ser334 and Thr189), p-AMPK (AMPKα and AMPKß1), synaptophysin, post-synaptic density protein 95 and p-cAMP-response element binding protein (p-CREB). The glial fibrillary acidic protein (GFAP) was determined using Western blotting and immunohistochemistry. RESULTS: BBR inhibited Aß expression in the brain of APP/PS1 mice. There was a strong up-regulation of both p-LKB1 (Ser334 and Thr189) and p-AMPK (AMPKα and AMPKß1) in the brains of APP/PS1 transgenic mice after BBR-treatment (P<0.01). BBR promoted the expression of synaptophysin, post-synaptic density protein 95 and p-CREB(Ser133) in the AD brain, compared with the model mice. CONCLUSION: BBR alleviates Aß pathogenesis and rescues synapse damage via activating LKB1/AMPK signaling in the brain of APP/PS1 transgenic mice.

Prevalence of white matter hyperintensities increases with age.

White matter hyperintensities (WMHs) that arise with age and/or atherosclerosis constitute a heterogeneous disorder in the white matter of the brain. However, the relationship between age-related risk factors and the prevalence of WMHs is still obscure. More clinical data is needed to confirm the relationship between age and the prevalence of WMHs. We collected 836 patients, who were treated in the Renmin Hospital, Hubei University of Medicine, China from January 2015 to February 2016, for a case-controlled retrospective analysis. According to T2-weighted magnetic resonance imaging results, all patients were divided into a WMHs group (n = 333) and a non-WMHs group (n = 503). The WMHs group contained 159 males and 174 females. The prevalence of WMHs increased with age and was associated with age-related risk factors, such as cardiovascular diseases, smoking, drinking, diabetes, hypertension and history of cerebral infarction. There was no significant difference in sex, education level, hyperlipidemia and hyperhomocysteinemia among the different age ranges. These findings confirm that age is an independent risk factor for the prevalence and severity of WMHs. The age-related risk factors enhance the occurrence of WMHs.

Exosomes: a novel therapeutic target for Alzheimer's disease?

Extracellular exosomes are formed inside the cytoplasm of cells in compartments known as multivesicular bodies. Thus, exosomes contain cytoplasmic content. Multivesicular bodies fuse with the plasma membrane and release exosomes into the extracellular environment. Comprehensive research suggests that exosomes act as both inflammatory intermediaries and critical inducers of oxidative stress to drive progression of Alzheimer's disease. An important role of exosomes in Alzheimer's disease includes the formation of neurofibrillary tangles and beta-amyloid production, clearance, and accumulation. In addition, exosomes are involved in neuroinflammation and oxidative stress, which both act as triggers for beta-amyloid pathogenesis and tau hyperphosphorylation. Further, it has been shown that exosomes are strongly associated with beta-amyloid clearance. Thus, effective measures for regulating exosome metabolism may be novel drug targets for Alzheimer's disease.

Different Expression Patterns of Amyloid-ß Protein Precursor Secretases in Human and Mouse Hippocampal Neurons: A Potential Contribution to Species Differences in Neuronal Susceptibility to Amyloid-ß Pathogenesis.

Extensive loss of hippocampal neurons serves a pathological basis for irreversible cognitive impairment in patients with Alzheimer's disease (AD). However, this characteristic cannot be replicated by transgenic mouse models, and its underlying mechanisms are unclear. Here, we present evidence that different expression patterns of amyloid-ß protein precursor (AßPP) secretases in human and mouse hippocampal neurons are a decisive cause of species difference in the susceptibility to Aß pathogenesis. Cell bodies of both pyramidal and granular neurons did not appear to undergo Aß deposits in the 10-month-old transgenic mutant human AßPP/presenilin-1 (PS1) mice. They expressed high levels of non-amyloidogenic α-secretase, and its neuroprotective products soluble AßPPα, but low levels of amyloidogenic ß-secretase and γ-secretase, and a neurotoxic product, Aß42 peptide. Unlike those found in the mouse, human hippocampal neuronal cell bodies expressed ß-secretase and γ-secretase, but not α-secretase, which could increase Aß generation, thus undergoing death in response to various pathological conditions. Increased hippocampal neuronal apoptosis at 48 h following local microinjection of α-secretase antibody ADAM10 into the hippocampus of AßPP/PS1 mice further suggests that high α-secretase expression in mouse neuronal cell bodies is a factor in the paucity of neuronal loss in AD-like pathology. Therefore, selective down-regulation of brain α-secretase in transgenic AD models will better replicate the disease spectrum, including decreased brain soluble AßPPα levels and massive neuronal loss in AD patients, and be beneficial for preclinical therapeutic evaluation of AD.

Polymorphism -116C/G of human X-box-binding protein 1 promoter is associated with risk of Alzheimer's disease.

AIM: Alzheimer's disease (AD) is a multifactor disease that has been reported to have a close association with endoplasmic reticulum (ER) stress response. In the response, the regulator factor human X-box-binding protein 1 (XBP1) has been shown to facilitate the refolding and degradation of misfolded proteins, prevent neurotoxicity of amyloid-beta (Aß) and tau, and play an important role in the survival of neurons. The aim in the study was to analyze the potential association between the -116C/G polymorphism of XBP1 and the risk of AD. METHODS: The association between -116C/G polymorphism of XBP1 promoter and possible risk of AD was assessed among 276 patients with AD and 254 matched healthy individuals in a case-control study. RESULTS: Overall, there was a significantly statistical difference in genotype (P = 0.0354) and allele frequencies (P = 0.0150, OR = 1.3642, 95% CI = 1.0618-1.7528) between the AD subjects and control subjects, showing that the -116C/G polymorphism of XBP1 might lead to increased susceptibility for AD in a Chinese Han population. In addition, the -116CG and -116GG genotypes were significantly associated with increased AD risk in female (P = 0.0217) and in subjects with APOE є4 (-) (P = 0.0070) in stratified analyses, and the -116CC genotype was significantly associated with fast cognitive deterioration in the AD patients (P = 0.0270). CONCLUSION: The study supports a role for the -116C/G polymorphism of XBP1 gene in the pathogenesis of AD, and further studies with a larger sample size and detailed data should be performed in other populations.

Minocycline reduces astrocytic reactivation and neuroinflammation in the hippocampus of a vascular cognitive impairment rat model.

OBJECTIVE: To study the neuroprotective mechanism of minocycline against vascular cognitive impairment after cerebral ischemia. METHODS: The rat model with vascular cognitive impairment was established by permanent bilateral common carotid artery occlusion (BCCAO). The observing time-points were determined at 4, 8 and 16 weeks after BCCAO. Animals were randomly divided into sham-operated group (n = 6), model group (subdivided into 3 groups: 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6), and minocycline group (subdivided into 3 groups: 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6). Minocycline was administered by douche via stomach after BCCAO until sacrifice. Glial fibrillary acidic protein (GFAP) was examined by Western blotting and immunohistochemistry. Levels of cyclooxygenase-2 (COX-2) and nuclear factor-kappaB (NF-kappaB) were measured by immunohistochemistry. IL-1beta and TNF-alpha levels were tested with ELISA method. RESULTS: Levels of GFAP, COX-2, NF-kappaB, IL-1beta and TNF-alpha were all up-regulated after permanent BCCAO, which could be significantly inhibited by minocycline. CONCLUSION: Minocycline could ameliorate the inflammation and oxidative stress in the hippocampus of the vascular cognitive impairment rat model.

Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion.

OBJECTIVE: Nitric oxide (NO) was speculated to play an important role in the pathophysiology of cerebral ischemia. Minocycline, a tetracycline derivative, reduced inflammation and protected against cerebral ischemia. To study the neuroprotection mechanism of minocycline for vascular dementia, the influences of minocycline on expressions of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) were observed in the brains of Wistar rats. METHODS: The vascular dementia rat model was established by permanent bilateral common carotid arteries occlusion (BCCAO). Wistar rats were divideded into 3 groups randomly: sham-operation group (S group), vascular dementia model group (M group), and minocycline treatment group (MT group). The behaviour was tested with Morris water maze and open-field task. Expressions of iNOS and eNOS were measured by immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). The optical density value was measured by imaging analysis. Percentage of positive cells with iNOS and eNOS expression was analyzed with optical microscope. RESULTS: Minocycline attenuated cognitive impairment. Inducible NOS was significantly down-regulated in MT group, compared with that in M group (P < 0.01), while eNOS was significantly up-regulated, compared with that in M group (P < 0.01). The expressions of iNOS and eNOS in M and MT groups were higher than those in S group (P < 0.01). CONCLUSION: Minocycline can down-regulate the expression of iNOS and up-regulate the expression of eNOS in vascular dementia, which restrains apoptosis and oxidative stress to protect neural function.

[Neural stem cell transplantation and nerve growth factor promote neurological recovery in rats with ischemic stroke].

OBJECTIVE: To observe the effect of neural stem cell (NSC) transplantation and nerve growth factor (NGF) on neurological function recovery in rats with ischemic stroke induced by transient middle cerebral artery occlusion (MCAO). METHODS: Cultured hippocampal NSCs isolated from neonate rats were labeled with BrdU. Sixty-four rats subjected to transient MCAO were randomized equally into 4 groups, namely group A (MCAO model group), group B (model group with NGF treatment, group C (model group with NSC transplantation), and group D (model group with both NGF and NSC transplantation). The neurological deficits of the rats were evaluated with neurological severity score (NSS) after the treatment, and the brain tissues were examined with immunohistochemical and immunofluorescent staining for BrdU and nestin expression. RESULTS: The NSS of rats in group D 2 and 4 weeks after transplantation was significantly lower than that in the other 3 groups (P<0.05), and the scores in groups B and C were significantly lower than those in group A (P<0.05). The number of BrdU- and nestin-positive cells was significantly greater in group B than in group A (P<0.05), and BrdU-positive cells were markedly more numerous in group D than in group C (P<0.05). CONCLUSION: Both NSC transplantation and NGF treatment can obviously improve the neurological function of rats after MCAO, but their combined use shows stronger effects. NGF can promote autologous NSC activation and proliferation, with also stimulatory effect on the proliferation of transplanted NSCs.