Meng-Shan Tan

Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy

Neurodegenerative diseases, such as Alzheimers disease Parkinsons disease, Huntingtons disease, and amyotrophic lateral sclerosis, share a common cellular and molecular pathogenetic mechanism involving aberrant misfolded protein or peptide aggregation and deposition. Autophagy represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Emerging studies have demonstrated that up-regulation of autophagy can lead to decreased levels of these toxic aggregate-prone proteins, and is beneficial in the context of aging and various models of neurodegenerative diseases. Understanding the signaling pathways involved in the regulation of autophagy is crucial to the development of strategies for therapy. This review will discuss the cellular and molecular mechanisms of autophagy and its important role in the pathogenesis of aging and neurodegenerative diseases, and the ongoing drug discovery strategies for therapeutic modulation.

Circulating miR-125b as a biomarker of Alzheimer's disease.

BACKGROUND MicroRNAs (miRNAs) are endogenous small RNAs of 21-25 nucleotides that post-transcriptionally regulate gene expressions. Recently, circulating miRNAs have been reported as promising biomarkers for neurodegenerative disorders and processes affecting the central nervous system. This study was conducted to investigate the potential role of serum miRNAs as diagnostic biomarkers for Alzheimers disease (AD). METHODS Serum samples were obtained from 105 probable AD patients and 150 age- and gender-matched normal controls. The serum concentrations of miRNAs miR-9, miR-29a, miR-29b, miR-101, miR-125b, and miR-181c were measured with a real-time quantitative reverse transcriptase PCR (qRT-PCR) method. RESULTS We found both miR-125b and miR-181c were down-regulated while miR-9 was up-regulated in serum of AD patients compared with that of normal controls. Among the receiver operating characteristic (ROC) results, miR-125b alone showed its priority with a specificity up to 68.3% and a sensitivity of 80.8%. Importantly, miR-125b was correlated with the Mini Mental State Examination (MMSE) in AD patients. CONCLUSIONS Our results indicate that serum miR-125b may serve as a useful noninvasive biomarker for AD.

Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre‐activation of AMPK‐dependent autophagy

Recent clinical trials report that metformin, an activator of AMP‐activated protein kinase (AMPK) used to treat type 2 diabetes, significantly reduces the risk of stroke by actions that are independent of its glucose‐lowering effects. However, the underlying molecular mechanisms are not known. Here, we tested the possibility that acute metformin preconditioning confers neuroprotection by pre‐activation of AMPK‐dependent autophagy in a rat model of permanent middle cerebral artery occlusion (pMCAO).

Upregulation of TREM2 Ameliorates Neuropathology and Rescues Spatial Cognitive Impairment in a Transgenic Mouse Model of Alzheimer's Disease

Triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for Alzheimer’s disease (AD), as its low-frequency variants increase the risk of this disease with an odds ratio similar to that of an APOE ɛ4 allele. To date, the expression and biologic functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was upregulated in microglia during disease progression. For the first time, we provided in vitro and in vivo evidence that this upregulation was attributed to the increased amyloid-β (Aβ)1–42 levels in the brain. By knockdown and overexpression of TREM2 in cultured primary microglia, we revealed that TREM2 modulated microglial functions under AD context, as it facilitated Aβ1–42 phagocytosis and inhibited Aβ1–42-triggered proinflammatory responses. Meanwhile, this modulation was dependent on DAP12, the adapter protein of TREM2. More importantly, overexpression of TREM2 in the brain of APPswe/PS1dE9 mice markedly ameliorated AD-related neuropathology including Aβ deposition, neuroinflammation, and neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive functions. Taken together, our data suggest that the upregulation of TREM2 serves as a compensatory response to Aβ1–42 and subsequently protects against AD progression by modulation of microglia functions. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a potential therapeutic target for this disease.

Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis

Objective Recently, several large randomised controlled trials about the treatments of cognitive impairment or dementia due to Parkinsons disease (CIND-PD or PDD) and dementia with Lewy bodies (DLB) were completed. Here, we systematically reviewed the studies (including the recent reports) to provide updated evidence for the treatments of CIND-PD, PDD and DLB. Methods We searched Cochrane Dementia and Cognitive Improvement Group Specialised Register, Pubmed, Embase, and other sources for eligible trials. We selected global impression and cognitive function as primary efficacy outcomes, and dropouts and adverse events as safety outcomes. Furthermore, Meta-analysis and trial sequential analysis (TSA) were used here. Results Ten trials were included in this study. Cholinesterase inhibitors and memantine produced small global efficacy on clinicians’ global impression of change (CGIC), from a weighted mean difference of −0.40 (95% CI −0.77 to −0.03) to −0.65 (95% CI −1.28 to −0.01); however, cholinesterase inhibitors but not memantine significantly improved cognition on Mini-Mental State Examination (MMSE), from 1.04 (95% CI 0.43 to 1.65) to 2.57 (95% CI 0.90 to 4.23). Additionally, both of them had good safety outcomes, although rivastigmine showed an increased risk on adverse events than placebo (risk ratio, RR 1.19, TSA adjusted 95% CI 1.04 to 1.36), these events were usually mild or moderate, and the risk disappeared on serious adverse events. Conclusions Cholinesterase inhibitors and memantine slightly improve global impression; however, only cholinesterase inhibitors enhance cognitive function. Besides, all the drugs have good safety outcomes. But the limited trials precluded the generalisation of these outcomes.

Genome-Wide Serum microRNA Expression Profiling Identifies Serum Biomarkers for Alzheimer's Disease

Recent findings that human serum contains stably expressed microRNAs (miRNAs) have revealed a great potential of serum miRNA signature as disease fingerprints to diagnosis. Here we used genome-wide serum miRNA expression analysis to investigate the value of serum miRNAs as biomarkers for the diagnosis of Alzheimers disease (AD). Illumina HiSeq 2000 sequencing followed by individual quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays was used to test the difference in levels of serum miRNAs between 50 AD patients and 50 controls in the screening stages. The detected serum miRNAs then were validated by qRT-PCR in 158 patients and 155 controls. MiR-98-5p, miR-885-5p, miR-483-3p, miR-342-3p, miR-191-5p, and miR-let-7d-5p displayed significantly different expression levels in AD patients compared with controls. Among the 6 miRNAs, miR-342-3p has the best sensitivity (81.5%) and specificity (70.1%) and was correlated to Mini-Mental State Examination score. This study identified six serum miRNAs that distinguish AD patients from healthy controls with high sensitivity and specificity. Serum miRNA panel (or miR-342-3p alone) may serve as a novel, noninvasive biomarker for AD.

Temsirolimus promotes autophagic clearance of amyloid-β and provides protective effects in cellular and animal models of Alzheimer's disease

Accumulation of amyloid-β peptides (Aβ) within brain is a major pathogenic hallmark of Alzheimers disease (AD). Emerging evidence suggests that autophagy, an important intracellular catabolic process, is involved in Aβ clearance. Here, we investigated whether temsirolimus, a newly developed compound approved by Food and Drug Administration and European Medicines Agency for renal cell carcinoma treatment, would promote autophagic clearance of Aβ and thus provide protective effects in cellular and animal models of AD. HEK293 cells expressing the Swedish mutant of APP695 (HEK293-APP695) were treated with vehicle or 100nM temsirolimus for 24h in the presence or absence of 3-methyladenine (5mM) or Atg5-siRNA, and intracellular Aβ levels as well as autophagy biomarkers were measured. Meanwhile, APP/PS1 mice received intraperitoneal injection of temsirolimus (20mg/kg) every 2 days for 60 days, and brain Aβ burden, autophagy biomarkers, cellular apoptosis in hippocampus, and spatial cognitive functions were assessed. Our results showed that temsirolimus enhanced Aβ clearance in HEK293-APP695 cells and in brain of APP/PS1 mice in an autophagy-dependent manner. Meanwhile, temsirolimus attenuated cellular apoptosis in hippocampus of APP/PS1 mice, which was accompanied by an improvement in spatial learning and memory abilities. In conclusion, our study provides the first evidence that temsirolimus promotes autophagic Aβ clearance and exerts protective effects in cellular and animal models of AD, suggesting that temsirolimus administration may represent a new therapeutic strategy for AD treatment. Meanwhile, these findings emphasize the notion that many therapeutic agents possess pleiotropic actions aside from their main applications.

Epigenetic mechanisms in Alzheimer's disease: implications for pathogenesis and therapy.

The vast majority of Alzheimers disease (AD) are late-onset forms (LOAD) likely due to the interplay of environmental influences and individual genetic susceptibility. Epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNAs, constitute dynamic intracellular processes for translating environmental stimuli into modifications in gene expression. Over the past decade it has become increasingly clear that epigenetic mechanisms play a pivotal role in aging the pathogenesis of AD. Here, we provide a review of the major mechanisms for epigenetic modification and how they are reportedly altered in aging and AD. Moreover, we also consider how aberrant epigenetic modifications may lead to AD pathogenesis, and we review the therapeutic potential of epigenetic treatments for AD.

Risk factors for predicting progression from mild cognitive impairment to Alzheimer’s disease: a systematic review and meta-analysis of cohort studies

Objective We sought to identify the risk factors for predicting the progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Methods We searched 6 electronic databases for cohort studies published from January 1966 to March 2015. Eligible studies were required to be relevant to the subject and provide sufficient data for our needs. Results 60 cohort studies with 14 821 participants from 16 countries were included in the meta-analysis. The strongest positive associations between risk factors and the progression from MCI to AD were found for abnormal cerebrospinal fluid (CSF), phosphorylated τ (p-τ) (relative risk (RR)=2.43, 95% CI=1.70 to 3.48), abnormal CSF τ/Aβ1–42 (RR=3.77, 95% CI=2.34 to 6.09), hippocampal atrophy (RR=2.59, 95% CI=1.95 to 3.44), medial temporal lobe atrophy (RR=2.11, 95% CI=1.70 to 2.63) and entorhinal atrophy (RR=2.03, 95% CI=1.57 to 2.62). Further positive associations were found for the presence of apolipoprotein E (APOE)ε4ε4 and at least 1 APOEε4 allele, CSF total-τ (t-τ), white matter hyperintensity volume, depression, diabetes, hypertension, older age, female gender, lower mini-mental state examination (MMSE) score and higher AD assessment scale cognitive subscale (ADAS-cog) score. Negative associations were found for high body mass index (RR=0.85, 95% CI=0.76 to 0.96) and higher auditory verbal learning test delay score (RR=0.86, 95% CI=0.77 to 0.96). Conclusions Patients with MCI with APOEε4, abnormal CSF τ level, hippocampal and medial temporal lobe atrophy, entorhinal atrophy, depression, diabetes, hypertension, older age, female gender, lower MMSE score and higher ADAS-cog score, had a high risk for the progression to AD.

Temsirolimus attenuates tauopathy in vitro and in vivo by targeting tau hyperphosphorylation and autophagic clearance

In a variety of neurodegenerative tauopathies including Alzheimers disease, frontotemporal dementia and some types of Parkinsons disease, tau protein is abnormally hyperphosphorylated by several kinases and eventually aggregates to form neurofibrillary tangles, a neurotoxic pathological characteristic that closely correlates with cognitive impairments. Hence, targeting hyperphosphorylated tau protein has now been considered as a valid therapeutic approach for these neurodegenerative tauopathies. As a newly developed analog of rapamycin, temsirolimus was approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of renal cell carcinoma. Recent findings suggested that temsirolimus also provided beneficial effects in animal models of Huntingtons disease and spinocerebellar ataxia type 3, two neurodegenerative diseases caused by accumulation of aberrant proteins within brain. To date, the therapeutic potentials of temsirolimus in neurodegenerative tauopathies have not been determined. Herein, we demonstrated for the first time that temsirolimus treatment effectively enhanced autophagic clearance of hyperphosphorylated tau in okadaic acid-incubated SH-SY5Y cells and in brain of P301S transgenic mice. Meanwhile, we showed that inactivation of glycogen synthase kinase-3β, the most important tau kinase, might contribute to the temsirolimus-induced reduction of tau hyperphosphorylation in these two tauopathy models. More importantly, temsirolimus administration rescued spatial learning and memory impairments in P301S transgenic mice. These findings highlight temsirolimus administration as a potential therapeutic strategy for neurodegenerative tauopathies.