Over-expression of miR-34a induces rapid cognitive impairment and Alzheimer's disease-like pathology.

Autosomal dominant Alzheimer disease (AD) is caused by rare mutations in one of three specific genes. This is in contrast to idiopathic, late-onset AD (LOAD), which has a more polygenetic risk profile and represents more than 95% of cases. Previously, we have demonstrated that increased expression of microRNA (miRNA)-34a (miR-34a) in AD brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Here we report the generation of a heterozygous, conditional miR-34a overexpression mouse (miR-34a+/-(TetR-TetO-miR-34a) Transgenic Mice). Doxycycline-treated mice of either sex exhibited profound behavioral impairment compared to untreated groups with only 1-2 months of over-expression of miR-34a. Cognitive impairment of individual mice in T- and Y-maze tasks correlated with elevated miR-34a expression in many parts of the brain including the hippocampus and prefrontal cortex, regions which are known to be involved in this task and implicated in LOAD dysfunction. Immunocytochemistry of brain sections from mice show high amyloid β and phosphorylated tau-specific staining in the hippocampus and cortex. Analysis of protein samples from these mice revealed that miR-34a targets specific genes involved in memory formation, amyloid precursor protein (APP) metabolism and phosphorylation-dephosphorylation of tau. Thus, our results suggest that the polygenetic dysfunction caused by miR-34a may occur in LOAD and disclose miR-34a as a potential therapeutic target. SIGNIFICANCE STATEMENT: Late-onset Alzheimer disease (LOAD) is associated with multiple gene alleles, a polygenetic profile of risk factors that is difficult to model in animals. Our approach to modeling LOAD was to produce a conditional over-expressing, miR-34a mouse using doxycycline-induction to activate expression. We observed that miR-34a over-expression results in a rapid cognitive impairment, associated with accumulation of intracellular Aβ and tau hyperphosphorylation in multiple brain regions. Targets for miR-34a, including ADAM10, NMDAR 2B, and SIRT1 RNAs, were profoundly reduced by miR-34a over-expression. Collectively, these results indicate that a rapid, profound cognitive decline and Alzheimer's disease neuropathology can be induced with miR-34a over-expression, suggesting that this animal model may represent a polygenetic risk factor model for LOAD.

Sarkar S ，Engler-Chiurazzi EB ，Cavendish JZ ，Povroznik JM ，Russell AE ，Quintana DD ，Mathers PH ，Simpkins JW ... -  《-》

Expression of microRNA-34a in Alzheimer's disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity.

Polygenetic risk factors and reduced expression of many genes in late-onset Alzheimer's disease (AD) impedes identification of a target(s) for disease-modifying therapies. We identified a single microRNA, miR-34a that is over expressed in specific brain regions of AD patients as well as in the 3xTg-AD mouse model. Specifically, increased miR-34a expression in the temporal cortex region compared to age matched healthy control correlates with severity of AD pathology. miR-34a over expression in patient's tissue and forced expression in primary neuronal culture correlates with concurrent repression of its target genes involved in synaptic plasticity, oxidative phosphorylation and glycolysis. The repression of oxidative phosphorylation and glycolysis related proteins correlates with reduced ATP production and glycolytic capacity, respectively. We also found that miR-34a overexpressed neurons secrete miR-34a containing exosomes that are taken up by neighboring neurons. Furthermore, miR-34a targets dozens of genes whose expressions are known to be correlated with synchronous activity in resting state functional networks. Our analysis of human genomic sequences from the tentative promoter of miR-34a gene shows the presence of NFκB, STAT1, c-Fos, CREB and p53 response elements. Together, our results raise the possibilities that pathophysiology-induced activation of specific transcription factor may lead to increased expression of miR-34a gene and miR-34a mediated concurrent repression of its target genes in neural networks may result in dysfunction of synaptic plasticity, energy metabolism, and resting state network activity. Thus, our results provide insights into polygenetic AD mechanisms and disclose miR-34a as a potential therapeutic target for AD.

Sarkar S ，Jun S ，Rellick S ，Quintana DD ，Cavendish JZ ，Simpkins JW ... -  《-》

miR-34a deficiency in APP/PS1 mice promotes cognitive function by increasing synaptic plasticity via AMPA and NMDA receptors.

MicroRNA (miR)-34a was recently determined to contribute to the pathological development of Alzheimer's disease (AD). miR-34a deficiency significantly attenuates cognitive deficits in amyloid precursor protein (APP)/presenilin 1 (PS1) mice; however, its role in early AD pathology and the underlying mechanisms remain elusive. Here, we confirmed that the increase of miR-34a expression in APP/PS1 mice was earlier than the relevant AD pathological characteristics, such as amyloid-β production, amyloid plaque deposition, and cognitive deficits. Furthermore, because predicted miR-34a target genes were broadly linked to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors, we evaluated synaptic plasticity by investigating high-frequency conditioning tetanus-induced excitatory postsynaptic potential, which revealed that synaptic plasticity was promoted in miR-34a knockout/APP/PS1 mice. Therefore, we assessed the expression of the presynaptic components synaptophysin and postsynaptic density protein 95 (PSD95) and found that synaptophysin and PSD95 were not altered by miR-34a deficiency. Additionally, the synaptic strength (vesicular fusion, vesicular docking, and transporting) was either not significantly changed. We also evaluated the levels of AMPA and NMDA receptors, which showed that the expression of AMPA and NMDA receptors was markedly upregulated in APP/PS1 mice with miR-34a deficiency. We conclude that miR-34a is involved in synaptic deficits in AD pathological development, which was, at least in part, due to the inhibition of NMDA (by miR-34a-5p) and AMPA (by miR-34a-3p) receptor expression.

Xu Y ，Chen P ，Wang X ，Yao J ，Zhuang S ... -  《-》

Cognitive Decline and Modulation of Alzheimer's Disease-Related Genes After Inhibition of MicroRNA-101 in Mouse Hippocampal Neurons.

Barbato C ，Giacovazzo G ，Albiero F ，Scardigli R ，Scopa C ，Ciotti MT ，Strimpakos G ，Coccurello R ，Ruberti F ... -  《-》

Micro-RNA-137 Inhibits Tau Hyperphosphorylation in Alzheimer's Disease and Targets the CACNA1C Gene in Transgenic Mice and Human Neuroblastoma SH-SY5Y Cells.

Jiang Y ，Xu B ，Chen J ，Sui Y ，Ren L ，Li J ，Zhang H ，Guo L ，Sun X ... -  《MEDICAL SCIENCE MONITOR》