Dataset Information

MicroRNA-34a (miRNA-34a) Mediated Down-Regulation of the Post-synaptic Cytoskeletal Element SHANK3 in Sporadic Alzheimer's Disease (AD).

ABSTRACT: Integrating a combination of bioinformatics, microRNA microfluidic arrays, ELISA analysis, LED Northern, and transfection-luciferase reporter assay data using human neuronal-glial (HNG) cells in primary culture we have discovered a set of up-regulated microRNAs (miRNAs) linked to a small family of down-regulated messenger RNAs (mRNAs) within the superior temporal lobe neocortex (Brodmann A22) of sporadic Alzheimer's disease (AD) brain. At the level of mRNA abundance, the expression of a significant number of human brain genes found to be down-regulated in sporadic AD neocortex appears to be due to the increased abundance of a several brain-abundant inducible miRNAs. These up-regulated miRNAs-including, prominently, miRNA-34a-have complimentary RNA sequences in the 3' untranslated-region (3'-UTR) of their target-mRNAs that results in the pathological down-regulation in the expression of important brain genes. An up-regulated microRNA-34a, already implicated in age-related inflammatory-neurodegeneration-appears to down-regulate key mRNA targets involved in synaptogenesis and synaptic-structure, distinguishing neuronal deficits associated with AD neuropathology. One significantly down-regulated post-synaptic element in AD is the proline-rich SH3 and multiple-ankyrin-repeat domain SHANK3 protein. Bioinformatics, microRNA array analysis and SHANK3-mRNA-3'UTR luciferase-reporter assay confirmed the importance of miRNA-34a in the regulation of SHANK3 expression in HNG cells. This paper reports on recent studies of a miRNA-34a-up-regulation coupled to SHANK3 mRNA down-regulation in sporadic AD superior-temporal lobe compared to age-matched controls. These findings further support our hypothesis of an altered miRNA-mRNA coupled signaling network in AD, much of which is supported, and here reviewed, by recently reported experimental-findings in the scientific literature.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC6374620 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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microRNA-34a (miRNA-34a) Mediated Down-Regulation of the Post-synaptic Cytoskeletal Element SHANK3 in Sporadic Alzheimer's Disease (AD).

Zhao Yuhai Y Jaber Vivian R VR LeBeauf Ayrian A Sharfman Nathan M NM Lukiw Walter J WJ

Frontiers in neurology 20190206

Integrating a combination of bioinformatics, microRNA microfluidic arrays, ELISA analysis, LED Northern, and transfection-luciferase reporter assay data using human neuronal-glial (HNG) cells in primary culture we have discovered a set of up-regulated microRNAs (miRNAs) linked to a small family of down-regulated messenger RNAs (mRNAs) within the superior temporal lobe neocortex (Brodmann A22) of sporadic Alzheimer's disease (AD) brain. At the level of mRNA abundance, the expression of a signific ...[more]

PMID: 30792687

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Project description:BACKGROUND:Down syndrome (DS), caused by chromosome 21 trisomy, is associated with an ultra-high risk of dementia due to Alzheimer's disease (AD), driven by amyloid precursor protein (APP) gene triplication. Understanding relevant molecular differences between those with DS, those with sporadic AD (sAD) without DS, and controls will aid in understanding AD development in DS. We explored group differences in plasma concentrations of amyloid-? peptides and tau (as their accumulation is a characteristic feature of AD) and cytokines (as the inflammatory response has been implicated in AD development, and immune dysfunction is common in DS). METHODS:We used ultrasensitive assays to compare plasma concentrations of the amyloid-? peptides A?40 and A?42, total tau (t-tau), and the cytokines IL1?, IL10, IL6, and TNF? between adults with DS (n =?31), adults with sAD (n =?27), and controls age-matched to the group with DS (n =?27), and explored relationships between molecular concentrations and with age within each group. In the group with DS, we also explored relationships with neurofilament light (NfL) concentration, due to its potential use as a biomarker for AD in DS. RESULTS:A?40, A?42, and IL1? concentrations were higher in DS, with a higher A?42/A?40 ratio in controls. The group with DS showed moderate positive associations between concentrations of t-tau and both A?42 and IL1?. Only NfL concentration in the group with DS showed a significant positive association with age. CONCLUSIONS:Concentrations of A?40 and A?42 were much higher in adults with DS than in other groups, reflecting APP gene triplication, while no difference in the A?42/A?40 ratio between those with DS and sAD may indicate similar processing and deposition of A?40 and A?42 in these groups. Higher concentrations of IL1? in DS may reflect an increased vulnerability to infections and/or an increased prevalence of autoimmune disorders, while the positive association between IL1? and t-tau in DS may indicate IL1? is associated with neurodegeneration. Finally, NfL concentration may be the most suitable biomarker for dementia progression in DS. The identification of such a biomarker is important to improve the detection of dementia and monitor its progression, and for designing clinical intervention studies.

Project description:One of the main components of senile plaques in Alzheimer's disease (AD)-affected brain is the Aβ peptide species harboring a pyroglutamate at position three pE3-Aβ. Several studies indicated that pE3-Aβ is toxic, prone to aggregation and serves as a seed of Aβ aggregation. The cyclisation of the glutamate residue is produced by glutaminyl cyclase, the pharmacological and genetic reductions of which significantly alleviate AD-related anatomical lesions and cognitive defects in mice models. The cyclisation of the glutamate in position 3 requires prior removal of the Aβ N-terminal aspartyl residue to allow subsequent biotransformation. The enzyme responsible for this rate-limiting catalytic step and its relevance as a putative trigger of AD pathology remained yet to be established. Here, we identify aminopeptidase A as the main exopeptidase involved in the N-terminal truncation of Aβ and document its key contribution to AD-related anatomical and behavioral defects. First, we show by mass spectrometry that human recombinant aminopeptidase A (APA) truncates synthetic Aβ1-40 to yield Aβ2-40. We demonstrate that the pharmacological blockade of APA with its selective inhibitor RB150 restores the density of mature spines and significantly reduced filopodia-like processes in hippocampal organotypic slices cultures virally transduced with the Swedish mutated Aβ-precursor protein (βAPP). Pharmacological reduction of APA activity and lowering of its expression by shRNA affect pE3-42Aβ- and Aβ1-42-positive plaques and expressions in 3xTg-AD mice brains. Further, we show that both APA inhibitors and shRNA partly alleviate learning and memory deficits observed in 3xTg-AD mice. Importantly, we demonstrate that, concomitantly to the occurrence of pE3-42Aβ-positive plaques, APA activity is augmented at early Braak stages in sporadic AD brains. Overall, our data indicate that APA is a key enzyme involved in Aβ N-terminal truncation and suggest the potential benefit of targeting this proteolytic activity to interfere with AD pathology.

Dataset Information

MicroRNA-34a (miRNA-34a) Mediated Down-Regulation of the Post-synaptic Cytoskeletal Element SHANK3 in Sporadic Alzheimer's Disease (AD).

Publications

microRNA-34a (miRNA-34a) Mediated Down-Regulation of the Post-synaptic Cytoskeletal Element SHANK3 in Sporadic Alzheimer's Disease (AD).

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