Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/β-secretase expression

Abstract

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...

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“…Previous reports demonstrate that miR-101 is downregulated in the temporal and parietal cortices of patients with AD. 32 Notably, miR-101 is shown to downregulate APP and fibrillar Ab in hippocampal neurons by directly targeting APP 33 or RanBP9, which encodes for the RanBP9 protein to enhance the proteolytic processing of APP and Ab generation both in vivo and in vitro. 34 In the present study, we demonstrate that miR-101b directly targets the 3 0 UTR of AMPK to post-transcriptionally regulate its protein levels.…”

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“…The miR-29a/b-1 cluster is decreased in sporadic AD patients, and it has been demonstrated that miR-29a/b-1 also regulates BACE1 expression (43). The study by Wang et al (46) demonstrated that miR-107 expression is decreased significantly in the cortex of AD patients, even at extremely early pathological alterations.…”

“…miR-298 and miR-328 play important roles by repressing the expression of β-amyloid precursor protein-converting enzyme 1 (BACE1), which causes amyloid-β (Aβ) overproduction in cultured neuronal cells (43). The miR-29a/b-1 cluster is decreased in sporadic AD patients, and it has been demonstrated that miR-29a/b-1 also regulates BACE1 expression (43).…”

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“…As miR-29a, miR-29b-1, and miR-9 were found to regulate BACE1 expression in reporter gene assays performed in transiently transfected HeLa cells, the miR-29a/b-1 cluster was significantly decreased in AD patients displaying abnormally high BACE1 protein levels (Hebert et al, 2008). Providing support for a causal relationship between miR-29a/b-1 expression and AD, these findings led the authors to propose that loss of specific miRNAs can contribute to increased BACE1 and Aβ levels in sporadic AD, as illustrated in Figure 1C.…”

“…Although a deficiency in Aβ clearance is certainly a possibility, an increased expression of the Aβ-producing enzyme BACE1 may also be an important contributor to the net accumulation of Aβ peptides and AD progression (Hebert et al, 2008). This assertion is supported by the observed dosage effect of BACE1 in inducing AD (Rovelet-Lecrux et al, 2006), suggesting that any alterations in BACE1 expression levels might contribute to the disease.…”