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.

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.

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.

[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.