Li-Ling Wang

The potential role of microRNA-146 in Alzheimer’s disease: Biomarker or therapeutic target?

Recently, there have been increasing evidences that microRNA-146 (miR-146) is related to up-regulated immune and inflammatory signaling through its target genes, such as IRAK1 and TRAF6. Additionally, abundant data continue to support the hypothesis that progressive up-regulation of inflammatory gene expression and elevated inflammatory signaling facilitate the development and progression of Alzheimers disease (AD). This review focuses on the recent findings regarding the role of miR-146 in modulating immune response and its subsequent effects in the pathogenesis of AD.

Melatonin for sleep disorders and cognition in dementia: a meta-analysis of randomized controlled trials.

The current review aims to examine melatonin therapy for both sleep disturbances and cognitive function in dementia. We searched all randomized controlled trials published in Medline, Embase, the Cochrane Library, China National Knowledge Infrastructure, the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register, and Clinical Trials.gov. The grading of recommendations assessment, development and evaluation framework was used to assess the quality of evidence. Seven studies were included (n = 520). Treated participants showed prolonged total sleep time (TST) by 24.36 minutes (P = .02). Sleep efficacy (SE) was marginally improved (P = .07). This effect was stronger under a longer intervention period lasting more than 4 weeks (P = .02). Conversely, cognitive function did not change significantly. Additionally, there was no report of severe adverse events. Given the current studies, we conclude that melatonin therapy may be effective in improving SE and prolonging TST in patients with dementia; however, there is no evidence that this improvement impacts cognitive function.

MicroRNA-922 promotes tau phosphorylation by downregulating ubiquitin carboxy-terminal hydrolase L1 (UCHL1) expression in the pathogenesis of Alzheimer's disease.

Decreased levels of soluble ubiquitin carboxy-terminal hydrolase L1 (UCHL1) have been reported in the brains of sporadic Alzheimers disease (AD) patients, and the introduction of UCHL1 rescued the synaptic and cognitive function of AD model mice. Obviously, a reduction in the levels of UCHL1 may play a role in the pathogenesis of AD. However, the mechanisms underlying the regulation of UCHL1 levels in AD have not been fully elucidated. MicroRNAs (miRs) have been shown to participate in the process of AD. In our study, we discovered that microRNA-922 decreased the levels of UCHL1. Neurofibrillary tangles (NFTs) mainly consisting of the hyperphosphorylated microtubule-associated protein tau are the defining pathological features of AD. In the present study, we found the levels of UCHL1 affected the levels of phosphorylated tau: the phosphorylated tau levels increased after knockdown of UCHL1 expression, and the phosphorylated tau levels decreased when UCHL1 was overexpressed. Furthermore, overexpression of microRNA-922 increased the phosphorylated tau levels. In conclusion, miR-922 increasing the levels of phosphorylated tau by regulating UCHL1 levels contributed to the pathogenesis of AD. Our study partly explained one of the mechanisms underlying the downregulation of UCHL1 levels in AD patients and could enrich the content of tau pathology in the pathogenesis of AD.

A single nucleotide polymorphism in LRP2 is associated with susceptibility to Alzheimer's disease in the Chinese population

BACKGROUND LRP2 (also called megalin) plays a potential key role in the pathogenesis of Alzheimers disease (AD). Recently, one genome-wide association study has revealed that the rs3755166 (G/A) polymorphism located in the LRP2 promoter is associated with development of AD in Caucasians, while there are no studies on the association LRP2 of with AD risk in Asians. METHODS To evaluate the relationship between the rs3755166 polymorphism of the LRP2 gene and AD in the ethnic Chinese Han, we conducted a case-control study (n=361, age>50) to determine the prevalence of one common single-nucleotide polymorphism (SNP) of LRP2 (rs3755166) in patients with AD in Chinese population of Mainland China, and clarified whether this polymorphism is a risk factor for AD. RESULTS The prevalence of the minor allele (A) in the rs3755166 polymorphism was significantly different in AD patients and control subjects (P<0.05). The rs3755166 polymorphism was associated with AD in the ethnic Chinese Han (OR=1.378, 95% CI: 1.017-1.867, P=0.039), and the results were not influenced by age, gender, or APOE status (P=0.441, P=0.94, P=0.432, respectively). CONCLUSION Our data revealed the allele (A) of the rs3755166 polymorphism within LRP2 gene may contribute to AD risk in the Chinese Han Population.

Cognitive impairment and the associated risk factors among the elderly in the Shanghai urban area: a pilot study from China

ObjectivesOur study aimed to investigate the prevalence of cognitive impairment(CI) and the associated risk factors among elderly people in Shanghai urban area, China.MethodsA population-based survey was conducted among people aged 55 years or older in urban areas of Shanghai. Face-to-face interviews were carried out to collect information including demographic characteristics, medical history, and medication use, etc. The validated Chinese version of the Mini-Mental State Examination(MMSE) was used to screen subjects with CI, and the criteria of CI were adjusted for education levels.ResultsA total of 3,176 home-living residents (≥55 years old) were included in the study. Among them, 266 people (102 men and 164 women) were identified as cognition impaired, with a prevalence of 8.38% (266/3,176, 95% CI: (8.26, 8.49)) for both genders, 9.21% (102/1,107,95% CI: (9.18, 9.33)) for men and 7.93% (164/2,069, 95% CI: (7.80, 8.09)) for women, respectively. Furthermore, we found that several significant risk factors, including social factors(education, number of children, marriage status, and family structure), physiological factors (age, blood glucose level, and obesity), factors on living styles(physical exercise, diet & chronic diseases), and genetic factor(ApoE), associated with CI onset.ConclusionsThis study confirms the high prevalence of CI among the elderly population in the Shanghai urban in China, similar to previous epidemiologic studies in Western countries. The putative risk factors associated with CI merit further investigated.

MicroRNA-146a suppresses ROCK1 allowing hyperphosphorylation of tau in Alzheimer's disease.

MicroRNA-146a is upregulated in the brains of patients with Alzheimer’s disease (AD). Here, we show that the rho-associated, coiled-coil containing protein kinase 1 (ROCK1) is a target of microRNA-146a in neural cells. Knockdown of ROCK1 mimicked the effects of microRNA-146a overexpression and induced abnormal tau phosphorylation, which was associated with inhibition of phosphorylation of the phosphatase and tensin homolog (PTEN). The ROCK1/PTEN pathway has been implicated in the neuronal hyperphosphorylation of tau that occurs in AD. To determine the function of ROCK1 in AD, brain tissue from 17 donors with low, intermediate or high probability of AD pathology were obtained and analyzed. Data showed that ROCK1 protein levels were reduced and ROCK1 colocalised with hyperphosphorylated tau in early neurofibrillary tangles. Intra-hippocampal delivery of a microRNA-146a specific inhibitor (antagomir) into 5xFAD mice showed enhanced hippocampal levels of ROCK1 protein and repressed tau hyperphosphorylation, partly restoring memory function in the 5xFAD mice. Our in vitro and in vivo results confirm that dysregulation of microRNA-146a biogenesis contributes to tau hyperphosphorylation and AD pathogenesis, and inhibition of this microRNA could be a viable novel in vivo therapy for AD.

Peripheral Blood MicroRNA Expression Profiles in Alzheimer’s Disease: Screening, Validation, Association with Clinical Phenotype and Implications for Molecular Mechanism

A series of investigations have been performed regarding microRNA (miRNA, miR) of Alzheimer’s disease (AD) patients. However, most of these used microarray with neither validation by PCR nor any follow-up on the biological mechanism implicated by findings. Further, there were rarely any analyses linking clinical phenotype of de novo, drug-naive patients to cellular pathogenic mechanism(s) to date. Microarray screening followed by validation via quantitative PCR (Q-PCR) assays and the relationship between miRNAs and phenotypic indices were evaluated. Additionally, the cellular mechanism of miRNAs through effects of β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) was assessed. We identified 2 specific differentially expressed (DE) miRNAs (miR-339 and miR-425) as potential diagnostic biomarkers for AD and revealed that these DE miRNAs could be involved in modulating the pathogenesis of AD via BACE1 protein inhibition. The findings presented here reveal a detailed snapshot of the profile of peripheral blood mononuclear cells (PBMC) miRNA changes in AD patients, association with clinical phenotype, and potential roles in cellular pathogenesis.

MicroRNA‐146a represses LRP2 translation and leads to cell apoptosis in Alzheimer's disease

MicroRNA regulation of transcript expression has been reported in patients with Alzheimers disease (AD). Here, we investigate the role of microRNA‐146a (miRNA‐146a), a brain‐enriched miRNA, which is upregulated in AD patients. Through analysis of predicted targets of miRNA‐146a, low‐density lipoprotein receptor‐related protein‐2 (Lrp2), a member of the LDLR family that is known to play a protective role in AD, was identified. Overexpression of miRNA‐146a in SH‐SY5Y cells significantly decreased Lrp2 expression, resulting in a reduction of Akt activation and induction of proapoptotic caspase‐3, thereby increasing cell apoptosis. Thus, specific miRNA‐146a regulation may contribute to AD by downregulating the Lrp2/Akt pathway.

The MTHFD1L gene rs11754661 marker is associated with susceptibility to Alzheimer's disease in the Chinese Han population

Our objective is to evaluate the relationship between the rs11754661 polymorphism of the MTHFD1L gene and Alzheimers disease (AD) in the ethnic Chinese Han. We conducted a case-control study (n=380, age>50) to determine the prevalence of one common single-nucleotide polymorphism (SNP) of MTHFD1L (rs11754661) in patients with AD in Chinese population of Mainland China, and clarified whether this polymorphism is a risk factor for AD. The prevalence of the minor allele (A) in the rs11754661 polymorphism was significantly different in AD patients and control subjects (P<0.01). The rs11754661 polymorphism was associated with AD in the ethnic Chinese Han (OR=1.829, 95% CI: 1.277-2.619, P=0.001), and the results were influenced by APOE status. Our data revealed that the allele (A) of the rs11754661 polymorphism within MTHFD1L gene may contribute to AD risk in the Chinese Han population.

Risk Factors for Cognitive Decline in Elderly People: Findings from the Two-year Follow-Up Study in Shanghai Urban Community

BACKGROUND The prevalence of cognitive impairment (CI) and its associated risk factors among elderly peoples in China has been investigated. However, dynamic studies revealing the risk factors associated with cognitive decline from follow-up observations in China are rarely performed. OBJECTIVE The present study aimed to identify factors predicting late-life cognitive decline in China. METHODS Participants were 223 community-dwelling residents (≥65 years old) from the urban community of Shanghai with no CI upon comprehensive assessments at baseline. Cognitive decline at 2-year follow-up was defined as a drop of two or more points from baseline score in the Mini-Mental State Examination (MMSE). Associations with baseline demographic, lifestyle, health, and medical factors were then determined within the population. RESULTS After 2 years, cognitive decline and incident CI developed in 75 (33.6%) and 25 (11.2%) participants, respectively. Across all participants, risk factors for cognitive decline included low education, high body mass index, and diabetes mellitus. Among participants with cognitive decline, points were predominantly lost in items relating to time orientation and complex commands in the MMSE. CONCLUSION This study confirms the differences in risk factors between cross-sectional and longitudinal studies for cognitive decline among the elderly population in urban Shanghai. Interventions tailored to potential risk factors associated with cognitive decline may offer further benefits.