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.