MicroRNAs in Alzheimer's disease

Delay, Charlotte; Mandemakers, Wim; Hébert, Sébastien S.

doi:10.1016/j.nbd.2012.01.003

Cited by 168 publications

(128 citation statements)

References 105 publications

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“…MicroRNAs (miRNAs) are a class of conserved, short, noncoding RNAs (4)(5)(6)(7)(8), many of which have demonstrated implications in AD (9)(10)(11). We have previously reported that miR-342-5p is up-regulated in APP/PS1, PS1ΔE9, and PS1-M146V transgenic AD mice, which is mechanistically linked to elevated β-catenin, c-Myc, and IFN regulatory factor (IRF)-9 (12).…”

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confidence: 99%

Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models

Sun

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Axon pathology has been widely reported in Alzheimer’s disease (AD) patients and AD mouse models. Herein we report that increased miR-342–5p down-regulates the expression of ankyrin G (AnkG), a protein known to play a critical role in establishing selective filtering machinery at the axon initial segment (AIS). Diminished AnkG expression leads to defective AIS filtering in cultured hippocampal neurons from AD mouse models, as monitored by selective exclusion of large macromolecules from the axons. Furthermore, AnkG-deficiency impairs AIS localization of Nav 1.6 channels and confines NR2B to the somatodendritic compartments. The expression of exogenous AnkG improved the cognitive performance of 12-mo-old APP/PS1 mice; thus, our data suggest that AnkG and impairment of AIS filtering may play important roles in AD pathology.

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confidence: 99%

Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models

Sun

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…miRNAs are emerging as potential key players in the pathogenesis of AD. 30 Various miRNA alterations have been identified in patients with AD and in mouse models of AD, 31 and most alterations have been implicated in the regulation of key AD genes. Previous reports demonstrate that miR-101 is downregulated in the temporal and parietal cortices of patients with AD.…”

Section: Discussionmentioning

confidence: 99%

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

Liú

Tang

et al. 2017

Molecular Therapy

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Histone deacetylase 2 (HDAC2) plays a major role in the epigenetic regulation of gene expression. Previous studies have shown that HDAC2 expression is strongly increased in Alzheimer's disease (AD), a major neurodegenerative disorder and the most common form of dementia. Moreover, previous studies have linked HDAC2 to Ab overproduction in AD; however, its involvement in tau pathology and other memoryrelated functions remains unclear. Here, we show that increased HDAC2 levels strongly correlate with phosphorylated tau in a mouse model of AD. HDAC2 overexpression induced AD-like tau hyperphosphorylation and aggregation, which were accompanied by a loss of dendritic complexity and spine density. The ectopic expression of HDAC2 resulted in the deacetylation of the hepatocyte nuclear factor 4a (HNF-4A) transcription factor, which disrupted its binding to the miR-101b promoter. The suppression of miR-101b caused an upregulation of its target, AMP-activated protein kinase (AMPK). The introduction of miR-101b mimics or small interfering RNAs (siRNAs) against AMPK blocked HDAC2-induced tauopathy and dendritic impairments in vitro. Correspondingly, miR-101b mimics or AMPK siRNAs rescued tau pathology, dendritic abnormalities, and memory deficits in AD mice. Taken together, the current findings implicate the HDAC2/miR-101/AMPK pathway as a critical mediator of AD pathogenesis. These studies also highlight the importance of epigenetics in AD and provide novel therapeutic targets.

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“…20 APP promotor screening has not yet been performed in CAA, to our knowledge. We and others have also shown that APP expression can be regulated by several miRNAs, and it has been hypothesized that genetic variations in the 3′UTR of APP that either abolish existing miRNA-binding sites or create illegitimate miRNA-binding sites could significantly contribute to the risk for disease (reviewed in Delay et al 24 and Long et al 25 ). Our previous studies reported that variants within the 3'UTR of APP, found in several patients with AD, can increase APP expression level in vitro, but these data could not be assessed in vivo.…”

Section: Discussionmentioning

confidence: 99%

Mutation in the 3’untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy

et al. 2015

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Aβ-related cerebral amyloid angiopathy (CAA) is a major cause of primary non-traumatic brain hemorrhage. In families with an early onset of the disease, CAA can be due to amyloid precursor protein (APP) pathogenic variants or duplications. APP duplications lead to a~1.5-fold increased APP expression, resulting in Aβ overproduction and deposition in the walls of leptomeningeal vessels. We hypothesized that rare variants in the 3'untranslated region (UTR) of APP might lead to APP overexpression in patients with CAA and no APP pathogenic variant or duplication. We performed direct sequencing of the whole APP 3'UTR in 90 patients with CAA and explored the functional consequences of one previously unreported variant. We identified three sequence variants in four patients, of which a two-base pair deletion (c.*331_*332del) was previously unannotated and absent from 175 controls of same ethnicity. This latter variant was associated with increased APP expression in vivo and in vitro. Bioinformatics and functional assays showed that the APP c.*331_*332del variant affected APP messenger RNA (mRNA) structure and binding of two microRNAs (miR-582-3p and miR-892b), providing a mechanism for the observed effects on APP expression. These results identify APP 3'UTR sequence variants as genetic determinants of Aβ-CAA.

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MicroRNAs in Alzheimer's disease

Cited by 168 publications

References 105 publications

Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models

Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

Mutation in the 3’untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy

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