Xiu-Qing Yao

A study on the association between infectious burden and Alzheimer's disease

Previous studies suggested that the overall burden of prior infections contributes to cardiovascular diseases and stroke. In the present study, the association between infectious burden (IB) and Alzheimers disease (AD) was examined.

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.

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.

Serum amyloid-beta levels are increased in patients with obstructive sleep apnea syndrome

A critical link between amyloid-beta (Aβ) and hypoxia has been demonstrated in in vitro and animal studies but has not yet been proven in humans. Obstructive sleep apnea syndrome (OSAS) is a common disorder that is characterized by nocturnal intermittent hypoxaemia. This study sought to examine the association between the chronic intermittent hypoxia and Aβ in OSAS patients. Forty-five cognitively normal OSAS patients and forty-nine age- and gender-matched subjects diagnosed with simple snoring and not OSAS were included in the present study. Serum Aβ40, Aβ42, total tau and phosphorylated tau 181 (P-tau 181) levels were measured using ELISA kits. All subjects were evaluated with nighttime polysomnography and cognitive tests. Compared with the controls, the OSAS patients exhibited significantly higher serum Aβ40, Aβ42 and total Aβ levels, and each of these levels was positively correlated with the apnea-hypopnea index, the oxygen desaturation index, and the mean and lowest oxyhaemoglobin saturations in the OSAS patients. Moreover, the OSAS patients exhibited strikingly higher serum P-tau 181 levels, and these levels were positively correlated with serum Aβ levels. This study suggests that there is an association between chronic intermittent hypoxia and increased Aβ levels, implying that hypoxia may contribute to the pathogenesis of Alzheimer’s disease.

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.

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.

Nutritional Deficiency in Early Life Facilitates Aging-Associated Cognitive Decline

BACKGROUND Nutrition is important for the fetal developmental programming. Nutritional deficiency in early life could increase the susceptibility to many aging-related disorders including cognitive decline. OBJECTIVE Our study aims to investigate the effect of early famine exposure on aging-associated cognitive function. METHODS We recruited 6790 subjects born between 1956 to 1964 during which the Great Chinese Famine occurred (1959-1961). Cognitive function of these subjects were evaluated using the Mini-Mental State Examination (MMSE), the Activities of Daily Living scale (ADL), the Instrumental Activities of Daily Living scale (IADL) and the Clinical Dementia Rating (CDR). RESULTS Our study identified that early exposure to the famine significantly increased the risk of cognitive impairments in later life, leading to higher prevalence of Mild Cognitive Impairment (MCI) and dementia. We also found the sex and rural-urban differences in this malnutrition-induced effect. Illiteracy, history of stroke or diabetes mellitus are great risk factors to facilitate the cognitive decline. CONCLUSION These findings demonstrate that exposure to famine during early life including prenatal period and early childhood facilitates aging-associated cognitive deficits.

Response to comment: 'Association between Helicobacter pylori burden and Alzheimer's disease'.

We appreciate Dr Kountouras et al.’s comment on our study showing the infectious burden of common pathogens including cytomegalovirus, herpes simplex virus type 1, Borrelia burgdorferi, Chlamydophila pneumoniae and Helicobacter pylori that are associated with Alzheimer’s disease (AD) [1]. It is intriguing to postulate that systemic infections may contribute to the development and/or progression of AD. The causative relation between systemic infections and AD and the relevant mechanisms remains unclear. The chronic inflammation or vascular diseases owing to systemic infection are possible approaches by which systemic infections contribute to AD [2]. Kountouras and colleagues found that infection of H. pylori, a common pathogen affecting humans, was associated with both AD and mild cognitive impairment [3, 4]. We agree with Kountouras’s hypothesis that H. pylori contributes to AD by sharing homologous epitopes with nerve components, thereby triggering autoimmune insults to brain neurons, and finally resulting in AD [5]. A recent study further links H. pylori infection with AD pathologies and suggests that intraperitoneal injection of H. pylori filtrate can promote Ab42 production by enhancing c-secretase and subsequently impairing cognitive performance in a rat model [6]. These studies suggest that autoimmune reactions to brain components might contribute to AD. Indeed, these common pathogens express proteins with marked homology to human antigens [7], thereby possibly causing autoimmune reactions via inducing brain-reactive autoantibodies. And this might be, at least in part, the source of ubiquitous brain-reactive autoantibodies (e.g. Ab) in human blood [8]. Increasing evidence indicates that autoantibodies might contribute to AD pathogenesis by increasing Ab deposition [8] and enhancing Ab toxicity [9]. Recently, we found that antibodies to the N-terminal of the Ab or APP672-699 region promote Ab production by enhancing b-site cleavage of amyloid-beta precursor protein [10]. Based on the above studies, autoimmune reactions induced by systemic infections might be an important pathogenesis of AD, which needs further investigation in the future.