Although the role of APP and PSEN genes in genetic Alzheimer's disease (AD) cases is well established, fairly little is known about the molecular mechanisms affecting A␤ generation in sporadic AD. Deficiency in A␤ clearance is certainly a possibility, but increased expression of proteins like APP or BACE1/␤-secretase may also be associated with the disease. We therefore investigated changes in microRNA (miRNA) expression profiles of sporadic AD patients and found that several miRNAs potentially involved in the regulation of APP and BACE1 expression appeared to be decreased in diseased brain. We show here that miR-29a, -29b-1, and -9 can regulate BACE1 expression in vitro. The miR-29a/b-1 cluster was significantly (and AD-dementia-specific) decreased in AD patients displaying abnormally high BACE1 protein. Similar correlations between expression of this cluster and BACE1 were found during brain development and in primary neuronal cultures. Finally, we provide evidence for a potential causal relationship between miR-29a/b-1 expression and A␤ generation in a cell culture model. We propose that loss of specific miRNAs can contribute to increased BACE1 and A␤ levels in sporadic AD.neurodegeneration ͉ amyloid ͉ noncoding RNA M utations in the APP and PSEN genes cause A␤ accumulation and familial Alzheimer's disease (AD) (1-4). However, little is known about the mechanisms that contribute to A␤ accumulation in the vast majority of sporadic AD cases. BACE1/␤-secretase cleavage of APP is the rate-limiting step for A␤ peptide production. Increased BACE1 expression is observed in patients with sporadic AD (5-8), and several mechanisms for this up-regulation have been proposed (9, 10). A link between BACE1 levels, A␤ load, and AD pathology has been reported (11), suggesting that increased BACE1 expression is indeed an important risk factor for sporadic AD.miRNAs are small noncoding RNAs that control gene expression at the posttranscriptional level by binding to the 3Ј untranslated region (3ЈUTR) of target mRNAs leading to their translational inhibition or sometimes degradation. Several miRNAs are specifically expressed or enriched in the brain (12-15), and some have been associated with neuronal differentiation, synaptic plasticity, and memory formation (16,17). The hypothesis that miRNA pathways could contribute to neurodegeneration is appealing (18) and has been tested to a certain degree in Drosophila (19) and mouse models (18,20,21) in which all miRNAs are lacking. Recently, Kim et al. (21) identified a subgroup of miRNAs, normally enriched in the midbrain, which expression is altered in sporadic Parkinson's disease (PD). One of the affected miRNAs, miR-133b, controls the differentiation and function of dopaminergic neurons (which are lost in PD). Here, we sought to investigate whether changes in miRNA expression exist in sporadic AD, and whether these changes could contribute to A␤ pathology. ResultsmiRNA Profile Analysis of Sporadic AD Brain. In a pilot study, we assessed the expression profiles of 328 human miRNAs f...

An overview of miRNAs altered in Alzheimer's disease (AD) was established by profiling the hippocampus of a cohort of 41 late-onset AD (LOAD) patients and 23 controls, showing deregulation of 35 miRNAs. Profiling of miRNAs in the prefrontal cortex of a second independent cohort of 49 patients grouped by Braak stages revealed 41 deregulated miRNAs. We focused on miR-132-3p which is strongly altered in both brain areas. Downregulation of this miRNA occurs already at Braak stages III and IV, before loss of neuron-specific miRNAs. Next-generation sequencing confirmed a strong decrease of miR-132-3p and of three family-related miRNAs encoded by the same miRNA cluster on chromosome 17. Deregulation of miR-132-3p in AD brain appears to occur mainly in neurons displaying Tau hyper-phosphorylation. We provide evidence that miR-132-3p may contribute to disease progression through aberrant regulation of mRNA targets in the Tau network. The transcription factor (TF) FOXO1a appears to be a key target of miR-132-3p in this pathway.

Type III RNase Dicer is responsible for the maturation and function of microRNA (miRNA) molecules in the cell. It is now well-documented that Dicer and the fine-tuning of the miRNA gene network are important for neuronal integrity. However, the underlying mechanisms involved in neuronal death, particularly in the adult brain, remain poorly defined. Here we show that the absence of Dicer in the adult forebrain is accompanied by a mixed neurodegenerative phenotype. Although neuronal loss is observed in the hippocampus, cellular shrinkage is predominant in the cortex. Interestingly, neuronal degeneration coincides with the hyperphosphorylation of endogenous tau at several epitopes previously associated with neurofibrillary pathology. Transcriptome analysis of enzymes involved in tau phosphorylation identified ERK1 as one of the candidate kinases responsible for this event in vivo. We further demonstrate that miRNAs belonging to the miR-15 family are potent regulators of ERK1 expression in mouse neuronal cells and co-expressed with ERK1/2 in vivo. Finally, we show that miR-15a is specifically downregulated in Alzheimer's disease brain. In summary, these results support the hypothesis that changes in the miRNA network may contribute to a neurodegenerative phenotype by affecting tau phosphorylation.

No abstract

Thymic output is a dynamic process, with high activity at birth punctuated by transient periods of involution during infection. Interferon-α (IFN-α) is a critical molecular mediator of pathogen-induced thymic involution, yet despite the importance of thymic involution, relatively little is known about the molecular integrators that establish sensitivity. Here we found that the Dicer-dependent microRNA network, and specifically miR-29a, was critical for reducing the sensitivity of the thymic epithelium to simulated infection signals, protecting the thymus against inappropriate involution. In the absence of Dicer or the miR-29a cluster in the thymic epithelium the amount of IFN-α receptor expressed by the thymic epithelium was increased, allowing suboptimal signals to trigger a rapid loss of thymic cellularity.

Chronic cardiac stress induces pathologic hypertrophy and fibrosis of the myocardium. The microRNA-29 (miR-29) family has been found to prevent excess collagen expression in various organs, particularly through its function in fibroblasts. Here, we show that miR-29 promotes pathologic hypertrophy of cardiac myocytes and overall cardiac dysfunction. In a mouse model of cardiac pressure overload, global genetic deletion of miR-29 or antimiR-29 infusion prevents cardiac hypertrophy and fibrosis and improves cardiac function. Targeted deletion of miR-29 in cardiac myocytes in vivo also prevents cardiac hypertrophy and fibrosis, indicating that the function of miR-29 in cardiac myocytes dominates over that in non-myocyte cell types. Mechanistically, we found cardiac myocyte miR-29 to de-repress Wnt signaling by directly targeting four pathway factors. Our data suggests that, cell- or tissue-specific antimiR-29 delivery may have therapeutic value for pathological cardiac remodeling and fibrosis.

The microRNA-29 (miR-29) family is among the most abundantly expressed microRNA in the pancreas and liver. Here, we investigated the function of miR-29 in glucose regulation using miR-29a/b-1 (miR-29a)-deficient mice and newly generated miR-29b-2/c (miR-29c)-deficient mice. We observed multiple independent functions of the miR-29 family, which can be segregated into a hierarchical physiologic regulation of glucose handling. miR-29a, and not miR-29c, was observed to be a positive regulator of insulin secretion in vivo, with dysregulation of the exocytotic machinery sensitizing β-cells to overt diabetes after unfolded protein stress. By contrast, in the liver both miR-29a and miR-29c were important negative regulators of insulin signaling via phosphatidylinositol 3-kinase regulation. Global or hepatic insufficiency of miR-29 potently inhibited obesity and prevented the onset of diet-induced insulin resistance. These results demonstrate strong regulatory functions for the miR-29 family in obesity and diabetes, culminating in a hierarchical and dose-dependent effect on premature lethality.

Recent research into the role of microRNA (miR) in the immune system has identified the miR-29 family as critical regulators of key processes in adaptive immunity. The miR-29 family consists of four members with shared regulatory capacity, namely miR-29a, miR-29b-1, miR-29b-2 and miR-29c. Being expressed in both T and B cells, as well as the main accessory cell types of thymic epithelium and dendritic cells, the miR-29 family has been identified as a putative regulator of immunity due to the predicted suppression of key immunological pathways. The generation of a series of in vivo molecular tools targeting the miR-29 family has identified the critical role of these miR in setting the molecular threshold for three central events in adaptive immunity: (1) control over thymic production of T cells by modulating the threshold for infection-associated thymic involution, (2) creating a neutral threshold for T cell polarization following activation, and (3) setting the threshold for B cell oncogenic transformation. These results identify the miR-29 family as potent immune modulators which have already been exploited through the evolution of a viral mimic and could potentially be exploited further for therapeutic intervention.