Amyloid ␤ (A␤) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in A␤ generation. Neuroinflammation potentially up-regulates BACE1 expression and increases A␤ production. In Alzheimer amyloid precursor protein-transgenic mice and SH-SY5Y cell models, we specifically knocked out or knocked down gene expression of mapk14, which encodes p38␣ MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunological and biochemical methods, we observed that reduction of p38␣ MAPK expression facilitated the lysosomal degradation of BACE1, decreased BACE1 protein and activity, and subsequently attenuated A␤ generation in the AD mouse brain. Inhibition of p38␣ MAPK also enhanced autophagy. Blocking autophagy by treating cells with 3-methyladenine or overexpressing dominant-negative ATG5 abolished the deficiency of the p38␣ MAPK-induced BACE1 protein reduction in cultured cells. Thus, our study demonstrates that p38␣ MAPK plays a critical role in the regulation of BACE1 degradation and A␤ generation in AD pathogenesis. Alzheimer disease (AD)2 is pathologically characterized by the extracellular deposits of amyloid ␤ peptide (A␤). A␤ injures neurons in the neocortex and limbic system directly (1) and indirectly by triggering microglial release of various neurotoxic inflammatory mediators, including cytokines (tumor necrosis factor-␣ and interleukin-1␤ (IL-1␤)) and reactive oxygen species (2). A␤ is generated after serial digestion of Alzheimer amyloid precursor protein (APP) by the membrane-anchored ␤-site APP-cleaving enzyme (BACE1, ␤-secretase) and ␥-secretase (3). It has been observed that knock-out of BACE1 or administration of the BACE1 inhibitor dramatically decreases A␤ levels in the brain and attenuates behavioral and electrophysiological deficits in APP-transgenic mice (4 -6). Thus, extensive investigations have focused on the direct inhibition of BACE1 to reduce A␤ load in the AD brain; however, these studies have unfortunately not yet led to any efficacious therapy for AD patients due to the various physiological roles of BACE1 (7). Using alternative methods to inhibit BACE1 might be a preferable investigative approach.Inflammatory activation might lead to up-regulation of neuronal BACE1 expression in the AD brain, as NF-B signaling enhances (8), and PPAR␥ activation suppresses (9), the activity of bace1 gene promoter. Accumulating evidence has shown that posttranslational modification of BACE1 is extremely important for the activity, intracellular trafficking, and lysosomal degradation of BACE1. For example, phosphorylation of BACE1 at Thr-252 by p25/Cdk5 increases the secretase activity (10), and phosphorylation at Ser-498 facilitates retrograde transport of BACE1 from endosomes to the trans-Golgi network (11). Ubiquitination at Lys-501 targets BACE1 to late endosomes/lysosomes for degradation (12). Finally, bisecting N-acetylglucosamine modification blocks delivery of BACE1 to lysosomes (13).p38 mitogen-activated protei...

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Alzheimer’s disease (AD) is characterized by intracellular neurofibrillary tangles. The primary component, hyperphosphorylated Tau (p-Tau), contributes to neuronal death. Recent studies have shown that autophagy efficiently degrades p-Tau, but the mechanisms modulating autophagy and subsequent p-Tau clearance in AD remain unclear. In our study, we first analyzed the relationship between the inflammatory activation and autophagy in brains derived from aged mice and LPS-injected inflammatory mouse models. We found that inflammatory activation was essential for activation of autophagy in the brain, which was neuronal ATG5-dependent. Next, we found that autophagy in cultured neurons was enhanced by LPS treatment of cocultured macrophages. In further experiments designed to provoke chronic mild stimulation of TLR4 without inducing obvious neuroinflammation, we gave repeated LPS injections (i.p., 0.15 mg/kg, weekly for 3 mo) to transgenic mice overexpressing human Tau mutant (P301S) in neurons. We observed significant enhancement of neuronal autophagy, which was associated with a reduction of cerebral p-Tau proteins and improved cognitive function. In summary, these results show that neuroinflammation promotes neuronal autophagy and that chronic mild TLR4 stimulation attenuates AD-related tauopathy, likely by activating neuronal autophagy. Our study displays the beneficial face of neuroinflammation and suggests a possible role in the treatment of AD patients.

Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-β (Aβ) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Aβ and p-Tau are two major pathogenic molecules with tau acting downstream to Aβ to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb 761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As potential therapeutic mechanisms, we demonstrated that treatment with EGb 761, especially the components of ginkgolide A, bilobalide, and flavonoids, but not with purified ginkgolide B or C, increased autophagic activity and degradation of p-Tau in lysosomes of neurons. Inhibiting ATG5 function or treating cells with Bafilomycin B1 abolished EGb 761-enhanced degradation of p-Tau in cultured neurons. Additionally, we observed that 5- instead of 2-month-treatment with EGb 761 inhibited the activity of p38-MAPK and GSK-3β. Therefore, long-term treatment with Ginkgo biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology through mechanisms against multiple AD pathogenic processes.

Alzheimer's disease (AD) remains a leading cause of dementia and no therapy that reverses underlying neurodegeneration is available. Recent studies suggest the protective role of artemisinin, an antimalarial drug, in neurological disorders. In this study, we investigated the therapeutic potential of artesunate, a water-soluble derivative of artemisinin, on amyloid-beta (Aβ)-treated challenged microglial BV-2, neuronal N2a cells, and the amyloid precursor protein/presenilin (APP/PS1) mice model. We found that Aβ significantly induced multiple AD-related phenotypes, including increased expression/production of pro-inflammatory cytokines from microglial cells, enhanced cellular and mitochondrial production of reactive oxygen species, promoted mitochondrial fission, inhibited mitochondrial fusion, suppressed mitophagy or biogenesis in both cell types, stimulated apoptosis of neuronal cells, and microglia-induced killing of neurons. All these in vitro phenotypes were attenuated by artesunate. In addition, the over-expression of the mitochondrial fission protein Drp-1, or down-regulation of the mitochondrial fusion protein OPA-1 both reduced the therapeutic benefits of artesunate. Artesunate also alleviated AD phenotypes in APP/PS1 mice, reducing Aβ deposition, and reversing deficits in memory and learning. Artesunate protects neuronal and microglial cells from AD pathology, both in vitro and in vivo. Maintaining mitochondrial dynamics and simultaneously targeting multiple AD pathogenic mechanisms are associated with the protective effects of artesunate. Consequently, artesunate may become a promising therapeutic for AD.

Hydrogen sulfide (H2S) is a novel gaseous transmitter, regulating a multitude of biological processes in the cardiovascular and other systems. However, it remains unclear whether it exerts any effect on arterial thrombosis. In this study, we examined the effect of H2S on ferric chloride (FeCl3)-induced thrombosis in the rat common carotid artery (CCA). The results revealed a decrease of the H2S-producing enzyme cystathionine γ-lyase (CSE) expression and H2S production that persisted until 48 h after FeCl3 application. Intriguingly, administration with NaHS at appropriate regimen reduced the thrombus formation and enhanced the blood flow, accompanied with the alleviation of CSE and CD31 downregulation, and endothelial cell apoptosis in the rat CCA following FeCl3 application. Moreover, the antithrombotic effect of H2S was also observed in Rose Bengal photochemical model in which the development of thrombosis is contributed by oxidative injury to the endothelium. The in vitro study demonstrated that the mRNA and protein expression of CSE, as well as H2S production, was decreased in hydrogen peroxide (H2O2)-treated endothelial cells. Exogenous supplement of NaHS and CSE overexpression consistently alleviated the increase of cleaved caspase-3 and endothelial cell damage caused by H2O2. Taken together, our findings suggest that endogenous H2S generation in the endothelium may be impaired during arterial thrombosis and that modulation of H2S, either exogenous supplement or boost of endogenous production, may become a potential venue for arterial thrombosis therapy.

Background: Cognitive decline (CD) occurs frequently in elderly patients with cerebral small vessel disease (CSVD). In China, elderly patients are more likely to enter healthcare in community hospitals where no magnetic resonance imaging (MRI) is available. This study aimed to explore the screening value of Sylvian fissure ratio (SFR) on CD and compare its gender difference from community-transferred patients.Methods: We performed a single-center, observational study (collected between April 1, 2016, and March 1, 2019) to evaluate the association between Montreal Cognitive Assessment (MoCA) and SFR in 203 eligible community-transferred patients. Baseline characteristics of patients were collected during hospitalization. Multiple linear regression analyses were used to estimate the effect of variables on MoCA, and interactions between select variables were analyzed in different models. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative effect of SFR to severe CD.Results: We identified that a meaningful SFR cutoff of 0.05 had important screening value (likelihood ratio test, p = 0.067) on CD. The ratio had a lower screen value in males when compared to females (adjusted β, −5.54; 95% CI, −8.78 to −2.30 vs. adjusted β, −1.01; 95% CI, −2.84 to 0.82). The gender difference was further verified by ROC curve analysis, in which this discriminative effect was more potent in females (from 0.878 to 0.948) compared to males (from 0.838 to 0.837).Conclusion: An SFR of 0.05 may be more useful to distinguish CD in female patients with CSVD than male patients in whom the syndrome is suspected clinically.

Objectives. Whether patent foramen ovale (PFO) closure is effective on migraine is controversial. This article was aimed at assessing the efficacy of PFO closure on migraine based on randomized controlled trials (RCTs) and observational studies. Methods. We searched PubMed, Embase, and Cochrane databases up to October 2020 evaluating PFO closure versus control in patients with migraine, then conducted a meta-analysis of all RCTs and observational studies, respectively. The main outcomes were (1) respond rate: complete cessation of migraine; (2) reduction in the frequency of migraine attacks per month; and (3) reduction in migraine days per month. Results. Seven studies (3 RCTs and 4 observational studies), containing 887 migraine patients, were identified. (1) The respond rate of PFO closure on migraine was significantly higher than control group both in RCT subgroup and observational studies subgroup (OR 3.86, 95% CI 1.35-11.04, P = 0.01 in RCTs; OR 8.28, 95% CI 2.31-29.67, P = 0.001 in observational studies). (2) Reduction in frequency of migraine attacks was higher in PFO closure group compared with control group in the RCT subgroup analysis ( mean   difference   MD = 0.57 , 95% CI 0.23-0.90, P = 0.0009 ). (3) Reduction in migraine days was also higher in PFO closure group compared with control group in the RCT subgroup analysis ( MD = 1.33 , 95% CI 0.35-2.31, P = 0.008 ). Conclusions. PFO closure might be suitable for migraine patients, especially for migraine with aura, by cessation of migraine headaches or reducing migraine attacks and migraine days.