MicroRNAs as diagnostic and therapeutic tools for Alzheimer's disease: advances and limitations
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摘要
Alzheimer's disease(AD) is the most common age-related, progressive neurodegenerative disease. It is characterized by memory loss and cognitive decline and responsible for most cases of dementia in the elderly. Late-onset or sporadic AD accounts for > 95% of cases, with age at onset > 65 years. Currently there are no drugs or other therapeutic agents available to prevent or delay the progression of AD. The cellular and molecular changes occurring in the brains of individuals with AD include accumulation of β-amyloid peptide and hyperphosphorylated tau protein, decrease of acetylcholine neurotransmitter, inflammation, and oxidative stress. Aggregation of β-amyloid peptide in extracellular plaques and the hyperphosphorylated tau protein in intracellular neurofibrillary tangles are characteristic of AD. A major challenge is identifying molecular biomarkers of the early-stage AD in patients as most studies have been performed with blood or brain tissue samples(postmortem) at late-stage AD. Subjects with mild cognitive impairment almost always have the neuropathologic features of AD with about 50% of mild cognitive impairment patients progressing to AD. They could provide important information about AD pathomechanism and potentially also highlight minimally or noninvasive, easy-to-access biomarkers. MicroRNAs are dysregulated in AD, and may facilitate the early detection of the disease and potentially the continual monitoring of disease progression and allow therapeutic interventions to be evaluated. Four recent reviews have been published of microRNAs in AD, each of which identified areas of weakness or limitations in the reported studies. Importantly, studies in the last three years have shown considerable progress in overcoming some of these limitations and identifying specific microRNAs as biomarkers for AD and mild cognitive impairment. Further large-scale human studies are warranted with less disparity in the study populations, and using an appropriate method to validate the findings.
Alzheimer's disease(AD) is the most common age-related, progressive neurodegenerative disease. It is characterized by memory loss and cognitive decline and responsible for most cases of dementia in the elderly. Late-onset or sporadic AD accounts for > 95% of cases, with age at onset > 65 years. Currently there are no drugs or other therapeutic agents available to prevent or delay the progression of AD. The cellular and molecular changes occurring in the brains of individuals with AD include accumulation of β-amyloid peptide and hyperphosphorylated tau protein, decrease of acetylcholine neurotransmitter, inflammation, and oxidative stress. Aggregation of β-amyloid peptide in extracellular plaques and the hyperphosphorylated tau protein in intracellular neurofibrillary tangles are characteristic of AD. A major challenge is identifying molecular biomarkers of the early-stage AD in patients as most studies have been performed with blood or brain tissue samples(postmortem) at late-stage AD. Subjects with mild cognitive impairment almost always have the neuropathologic features of AD with about 50% of mild cognitive impairment patients progressing to AD. They could provide important information about AD pathomechanism and potentially also highlight minimally or noninvasive, easy-to-access biomarkers. MicroRNAs are dysregulated in AD, and may facilitate the early detection of the disease and potentially the continual monitoring of disease progression and allow therapeutic interventions to be evaluated. Four recent reviews have been published of microRNAs in AD, each of which identified areas of weakness or limitations in the reported studies. Importantly, studies in the last three years have shown considerable progress in overcoming some of these limitations and identifying specific microRNAs as biomarkers for AD and mild cognitive impairment. Further large-scale human studies are warranted with less disparity in the study populations, and using an appropriate method to validate the findings.
Alzheimer's disease(AD) is the most common age-related, progressive neurodegenerative disease. It is characterized by memory loss and cognitive decline and responsible for most cases of dementia in the elderly. Late-onset or sporadic AD accounts for > 95% of cases, with age at onset > 65 years. Currently there are no drugs or other therapeutic agents available to prevent or delay the progression of AD. The cellular and molecular changes occurring in the brains of individuals with AD include accumulation of β-amyloid peptide and hyperphosphorylated tau protein, decrease of acetylcholine neurotransmitter, inflammation, and oxidative stress. Aggregation of β-amyloid peptide in extracellular plaques and the hyperphosphorylated tau protein in intracellular neurofibrillary tangles are characteristic of AD. A major challenge is identifying molecular biomarkers of the early-stage AD in patients as most studies have been performed with blood or brain tissue samples(postmortem) at late-stage AD. Subjects with mild cognitive impairment almost always have the neuropathologic features of AD with about 50% of mild cognitive impairment patients progressing to AD. They could provide important information about AD pathomechanism and potentially also highlight minimally or noninvasive, easy-to-access biomarkers. MicroRNAs are dysregulated in AD, and may facilitate the early detection of the disease and potentially the continual monitoring of disease progression and allow therapeutic interventions to be evaluated. Four recent reviews have been published of microRNAs in AD, each of which identified areas of weakness or limitations in the reported studies. Importantly, studies in the last three years have shown considerable progress in overcoming some of these limitations and identifying specific microRNAs as biomarkers for AD and mild cognitive impairment. Further large-scale human studies are warranted with less disparity in the study populations, and using an appropriate method to validate the findings.
引文
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Dorszewska J,Prendecki M,Oczkowska A,Dezor M,Kozubski W(2016)Molecular basis of familial and sporadic Alzheimer’s disease.Curr Alzheimer Res 13:952-963.
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Fagan AM,Perrin RJ(2012)Upcoming candidate cerebrospinal fluid biomarkers of Alzheimer’s disease.Biomark Med 6:455-476.
Galasko D(1998)An integrated approach to the management of Alzheimer’s disease:assessing cognition,function and behavior.Eur J Neurol 5:S9-S17.
Garcia-Ptacek S,Eriksdotter M,Jelic V,Porta-Etessam J,K?reholt I,Manzano Palomo S(2016)Subjective cognittive impairment:towards early identification of Alzheimer’s disease.Neurologia 31:562-571.
G?tz J,Deters N,Doldissen A,Bokhari L,Ke Y,Wiesner A,Schonrock N,Ittner LM(2007)A decade of tau transgenic animal models and beyond.Brain Pathol 17:91-103.
Guo H,Ingolia NT,Weissman JS,Bartel DP(2010)Mammalian microRNAs predominantly act to decrease target mRNA levels.Nature 466:835-840.
Hara N,Kikuchi M,Miyashita A,Hatsuta H,Saito Y,Kasuga K,Murayama S,Ikeuchi T,Kuwano R(2017)Serum microRNA miR-501-3p as a potential biomarker related to the progression of Alzheimer’s disease.Acta Neuropathol Commun 5:10
Holzman DM(2011)CSF biomarkers for Alzheimer’s disease:current utility and potential future use.Neurobiol Aging 32:S4-S9.
Hu Z,Zhao J,Hu T,Luo Y,Zhu J,Li Z(2015)miR-501-3p mediates the activity-dependent regulation of the expression of AMPA receptor subunit Glu A1.J Cell Biol 208:949-959.
Jia LH,Liu YN(2016)Downregulated serum miR-223 serves as biomarker in Alzheimer’s disease.Cell Biochem Funct 34:233-237.
Kayano M,Higaki S,Satoh JI,Matsumoto K,Matsubara E,Takikawa O,Niida S(2016)Plasma microRNA biomarker detection for mild cognitive impairment using differential correlation analysis.Biomark Res 4:22.
Keller A,Backes C,Haas J,Leidinger P,Maetzler W,Deuschle C,Berg D,Ruschil C,Galata V,Ruprecht K,St?hler C,Würstle M,Sickert D,Gogol M,Meder B,Meese E(2016)Validating Alzheimer’s disease micro RNAs using next-generation sequencing.Alzheimers Dement 12:565-576.
Kerr F,Rickle A,Nayeem N,Brandner S,Cowburn RF,Lovestone S(2006)PTEN,a negative regulator of PI3 kinase signalling,alters tau phophorylation in cells by mechanisms independent of GSK-3.FEBS Lett 580:3121-3128.
Kruman II,Wersto RP,Cardozo-Pelaez F,Smilenov L,Chan SL,Chrest FJ,Emokpae R Jr,Gorospe M,Mattson MP(2004)Cell cycle activation linked to neuronal cell death initiated by DNA damage.Neuron 41:549-561.
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