Ye-Ran Wang

Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits

Significance Alzheimer’s disease (AD) is a devastating disease that results in the progressive cognitive deficits of elderly and has become one of major social and economic burdens worldwide. There is no effective drug or therapy to prevent or halt the progressive cognitive dysfunctions due to the complex mechanisms such as accumulation of amyloid-β (Aβ), increase in oxidative stress, and formation of neurofibrillary tangle that drive the development of the disease. We found here that Edaravone, a drug that has been used for ischemic stroke, is able to prevent and treat AD by targeting multiple pathways of AD pathogenesis and rescuing the cognitive deficits of a mouse model of AD. Our study suggests Edaravone is a promising drug candidate for AD. Alzheimer’s disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.

Clearance of Amyloid-Beta in Alzheimer’s Disease: Shifting the Action Site from Center to Periphery

Amyloid-beta (Aβ) is suggested to play a causal role in the pathogenesis of Alzheimer’s disease (AD). Immunotherapies are among the most promising Aβ-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including Aβ vaccination (AN1792), anti-Aβ antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to Aβ oligomerization from plaques, neuroinflammation related to opsonized Aβ phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral Aβ clearance would be effective and safe for future Aβ-targeting therapies.

Amyloid beta1–42 (Aβ42) up‐regulates the expression of sortilin via the p75NTR/RhoA signaling pathway

Sortilin, a Golgi sorting protein and a member of the VPS10P family, is the co‐receptor for proneurotrophins, regulates protein trafficking, targets proteins to lysosomes, and regulates low density lipoprotein metabolism. The aim of this study was to investigate the expression and regulation of sortilin in Alzheimers disease (AD). A significantly increased level of sortilin was found in human AD brain and in the brains of 6‐month‐old swedish‐amyloid precursor protein/PS1dE9 transgenic mice. Aβ42 enhanced the protein and mRNA expression levels of sortilin in a dose‐ and time‐dependent manner in SH‐SY5Y cells, but had no effect on sorLA. In addition, proBDNF also significantly increased the protein and mRNA expression of sortilin in these cells. The recombinant extracellular domain of p75NTR (P75ECD‐FC), or the antibody against the extracellular domain of p75NTR, blocked the up‐regulation of sortilin induced by Amyloid‐β protein (Aβ), suggesting that Aβ42 increased the expression level of sortilin and mRNA in SH‐SY5Y via the p75NTR receptor. Inhibition of ROCK, but not Jun N‐terminal kinase, suppressed constitutive and Aβ42‐induced expression of sortilin. In conclusion, this study shows that sortilin expression is increased in the AD brain in human and mice and that Aβ42 oligomer increases sortilin gene and protein expression through p75NTR and RhoA signaling pathways, suggesting a potential physiological interaction of Aβ42 and sortilin in Alzheimers disease.

Sex Dimorphism Profile of Alzheimer's Disease-Type Pathologies in an APP/PS1 Mouse Model

Alzheimer’s disease (AD) is the most common form of dementia among the elderly, characterized by parenchymal and vascular beta-amyloid (Aβ) burden, tau pathology, neuroinflammation, and loss of neurons and synapses. There is a clear sex difference in the prevalence of AD. However, sex differences in AD-type pathologies have not been systematically documented. Applying 12-month-old female and male APP/PS1 mice as a model, we investigated the sex dimorphism in these major pathological indices. Compared with male APP/PS1 mice, the females exhibited higher parenchymal Aβ burdens, with the sex difference in hippocampus being the most significant. Female APP/PS1 mice had more severe cerebral amyloid angiopathy and subsequent microhemorrhage. In addition, female APP/PS1 mice also showed higher levels of phosphorylated tau and proinflammatory cytokines, more severe astrocytosis and microgliosis, and greater neuronal and synaptic degenerations. The present study systematically described a sex dimorphism in AD-type pathologic indices, suggesting that gender should be taken into account in designing studies involving these pathological indices and when interpreting the relevant findings in those studies.

Association Between Serum Amyloid-Beta and Renal Functions: Implications for Roles of Kidney in Amyloid-Beta Clearance.

Amyloid-beta (Aβ) plays a central role in the pathogenesis of Alzheimer’s disease (AD), and it is a major therapeutic target for AD. It is proposed that removal of Aβ in blood can facilitate Aβ clearance from the brain, representing a promising therapeutic approach for AD. However, the efficacy and mechanisms for Aβ clearance by peripheral organs and tissues remain largely unknown. In the present study, 47 chronic kidney disease (CKD) patients (16 newly diagnosed patients who had never been dialyzed and 31 patients who were receiving dialysis) and 43 normal controls (NC) were enrolled. We found that serum Aβ levels were significantly higher in CKD patients than NC. CKD patients who were receiving dialysis had lower serum Aβ levels than patients without receiving dialysis, being comparable to NC. Furthermore, serum Aβ levels were correlated with renal functions reflected by estimated glomerular filtration rate (eGFR) and residual GFR (rGFR). Our study suggests that kidney is involved in peripheral clearance of Aβ, and dialysis might be a potential therapeutic approach of Aβ removal.

An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect.

BackgroundSenile plaques consisting of amyloid-beta (Aβ) are the major pathological hallmark of Alzheimer’s disease (AD) and have been the primary therapeutic target. Immunotherapies, which are designed to remove brain Aβ deposits, increased levels of soluble Aβ and accelerated brain atrophy in some clinical trials, suggesting that the solubilization of Aβ deposition might facilitate the formation of more toxic Aβ oligomers and enhance neurotoxicity.MethodsThe capacity of antibodies against different epitopes of Aβ to disaggregate preformed Aβ fibrils was investigated. The co-incubation of antibodies and Aβ fibrils was then tested for neurotoxicity both in vitro and in vivo.ResultsAfter the incubation of preformed Aβ fibrils with the N-terminal antibody 6E10, the fibrils were decreased, while the oligomers, mostly dimers and trimers, were significantly increased. However, no such effects were observed for antibodies targeting the middle domain (4G8) and C-terminus of Aβ (8G7). The co-incubates of preformed Aβ fibrils with 6E10 were more neurotoxic, both in vitro and in vivo, than the co-incubates with 4G8 and 8G7.ConclusionsOur results indicate that the antibody targeting the N-terminus of Aβ promoted the transformation of Aβ from fibrils into oligomers and increased neurotoxicity. Immunotherapies should take into consideration the enhanced neurotoxicity associated with the solubilization of Aβ deposits by antibodies against the Nterminus of Aβ.

Associations Between ApoEε4 Carrier Status and Serum BDNF Levels—New Insights into the Molecular Mechanism of ApoEε4 Actions in Alzheimer’s Disease

Insufficient neurotrophic support increases the risk for developing Alzheimer’s disease (AD). Mounting evidence has confirmed the association of brain-derived neurotrophic factor (BDNF) and apolipoprotein E (ApoE) with AD. As both BDNF and ApoE are suggested to be involved in modulating brain integrity, the present study is aiming to investigate the associations between these two factors. In this study, 110 AD patients and 120 cognitively normal controls (NC) were recruited for measurement of serum BDNF levels and ApoE genotyping. Serum BDNF levels in the AD group were significantly lower than that in the NC group, reflecting insufficient neurotrophic supply in AD patients. We further found that ApoE ε4+/− and ε4+/+ subjects had significantly lower serum BDNF levels than ε4−/− subjects in the whole cohort and the NC group, suggesting altered BDNF metabolism in ApoE ε4 carriers. Further analysis indicated possible interactions between ApoEε4 and BDNF in their co-effects on AD and mini-mental state examination (MMSE) scores. Our findings imply that the possible involvement of ApoE ε4 in BDNF metabolism might be another molecular mechanism underlying the contribution of ApoE ε4 to the development of AD.

The relationship between single nucleotide polymorphisms of the NTRK2 gene and sporadic Alzheimer's disease in the Chinese Han population

Alzheimers disease (AD) is characterized by the degeneration of basal forebrain cholinergic neurons, whose survival and function are affected by neurotrophins and their receptors. The impaired signaling pathway of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) is considered to play an important role in AD pathogenesis. To explore the association of polymorphisms within the NTRK2 gene (encoding TrkB) and sporadic AD (sAD), a case-control study was conducted in a Chinese Han cohort including 216 sAD patients and 244 control participants. Five single nucleotide polymorphisms (SNPs), with four of them within the promoter region and one in intron, were selected and genotyped with a polymerase chain reaction-ligase detection reaction (PCR-LDR) method. No association was revealed between these SNPs or the haplotypes containing four promoter SNPs and the risk of sAD. The results of this study indicate that polymorphisms in the selected regions of the NTRK2 gene are unlikely to confer the susceptibility of sAD in the Chinese Han population.

No association of SORT1 gene polymorphism with sporadic Alzheimer's disease in the Chinese Han population.

Increasing evidence shows that sortilin (encoded by SORT1 gene), a member of the vacuolar protein sorting 10 family of sorting receptors, can modulate amyloid-&bgr; peptides (A&bgr;) metabolism and clearance, as well as mediate the neurotoxicity of the A&bgr; oligomer and proneurotrophins, thus playing diverse roles in the pathogenesis of Alzheimer’s disease. To assess the association between single nucleotide polymorphism (SNP) of the SORT1 gene and sporadic Alzheimer’s disease (sAD) in the Chinese Han population, a case–control study was carried out including 220 sAD patients and 245 controls. One tag SNP was selected from the entire SORT1 gene through construction of linkage disequilibrium blocks, and three SNPs located in the vicinity of SORT1 that affect its expression were also selected. The four target SNPs were genotyped using a multiplex PCR-ligase detection reaction method, yielding no significant association between them or haplotypes containing three of them, and the risk of sAD. The results of this study indicate that polymorphisms of the SORT1 gene are unlikely to confer the risk of sAD in the Chinese Han population.

Associations Between Hepatic Functions and Plasma Amyloid-Beta Levels—Implications for the Capacity of Liver in Peripheral Amyloid-Beta Clearance

Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). Clearance of Aβ is a promising therapeutic strategy for AD. We have previously demonstrated that peripheral organs play important roles in the clearance of brain-derived Aβ. In the present study, we recruited 46 patients with liver cirrhosis and 46 normal controls and found that plasma Aβ40 and Aβ42 levels were significantly higher in the cirrhosis patients than in the normal controls. Notably, cirrhosis patients with hepatitis B virus (HBV) infection had higher plasma Aβ40 and Aβ42 levels than HBV-negative cirrhosis patients. Besides, cirrhosis patients had significantly higher plasma levels of interleukin-1β (IL-1β) and IL-6. Plasma tumor necrosis factor α (TNF-α) and interferon-γ (IFN-γ) levels were not significantly different between the groups. Moreover, we found significant correlations of hepatic functions with plasma Aβ40 and Aβ42 levels. Plasma IL-6 levels were also significantly correlated with plasma Aβ40 levels. However, in the linear regression model, we found significant correlation of plasma Aβ40 levels with hepatic functions, but not with plasma IL-6 levels. Our results indicate that the hepatic dysfunctions might result in decreased peripheral Aβ clearance by the liver. Protecting hepatic functions might be helpful for the clearance of brain-derived Aβ in the blood.