Bart De Strooper and his collaborators have characterized a microRNA cluster (miR29a/b-1) that is significantly and specifically downregulated in AD patients. miRNAs are extremely important regulators of gene expression that modulate both translation efficiency and stability of their target mRNAs. Importantly, the miRNA studied by De Strooper's group regulates the β-secretase BACE1. Downregulation of the miRNA cluster correlates with increased expression of BACE1 in AD patients, as well as during development and in primary cells. BACE1 mRNA is apparently not destabilized, indicating that in this case the miRNA controls the translation of the mRNA. If this control is lost, due to a decrease of miRNA expression, an excess of BACE1 is expressed, which will increase the malign processing of APP to form the AD-causing Aβ peptide.

First, this work further establishes BACE1 as a causative agent and hence drug target in AD. In this respect, it is also interesting that this effect is specific to AD patients and not seen in other forms of dementia. Second, this work, together with a...  Read more

Bart De Strooper and his collaborators have characterized a microRNA cluster (miR29a/b-1) that is significantly and specifically downregulated in AD patients. miRNAs are extremely important regulators of gene expression that modulate both translation efficiency and stability of their target mRNAs. Importantly, the miRNA studied by De Strooper's group regulates the β-secretase BACE1. Downregulation of the miRNA cluster correlates with increased expression of BACE1 in AD patients, as well as during development and in primary cells. BACE1 mRNA is apparently not destabilized, indicating that in this case the miRNA controls the translation of the mRNA. If this control is lost, due to a decrease of miRNA expression, an excess of BACE1 is expressed, which will increase the malign processing of APP to form the AD-causing Aβ peptide.

First, this work further establishes BACE1 as a causative agent and hence drug target in AD. In this respect, it is also interesting that this effect is specific to AD patients and not seen in other forms of dementia. Second, this work, together with a parallel study published almost at the same time (Wang et al., 2008), for the first time associates a dysregulation of miRNAs with AD development in humans.

Gene regulation by miRNAs is still a new and poorly understood field, and to have such a strong link to an important human pathology will certainly encourage further studies into the topic.

View all comments by Claudia Bagni

An excellent piece of work by Sebastien, Bart, and colleagues. This study underscores the role of BACE elevation in late-onset AD (LOAD).

This study from Bart's group and the recent work from Karen Duff's group on Cdk5's role in BACE transcription (Wen et al., 2008) now show that BACE levels could be regulated by distinct mechanisms acting either at the level of translation or transcription. Upregulation of BACE, either in terms of the enzymatic activity or protein levels, is clearly a risk for LOAD. Hence, understanding the mechanisms by which BACE is upregulated is crucial for AD etiology and also for therapy.

Bob Vassar's results on stress-induced eIF2a phosphorylation causing an increase in BACE levels also come timely [see ARF related Keystone story]. It would be interesting to find mechanisms that cause this eIF2a phosphorylation-induced switch to specific translation. Since cellular stress regulates miRNA levels, it would be interesting to see if there is...  Read more

An excellent piece of work by Sebastien, Bart, and colleagues. This study underscores the role of BACE elevation in late-onset AD (LOAD).

This study from Bart's group and the recent work from Karen Duff's group on Cdk5's role in BACE transcription (Wen et al., 2008) now show that BACE levels could be regulated by distinct mechanisms acting either at the level of translation or transcription. Upregulation of BACE, either in terms of the enzymatic activity or protein levels, is clearly a risk for LOAD. Hence, understanding the mechanisms by which BACE is upregulated is crucial for AD etiology and also for therapy.

Bob Vassar's results on stress-induced eIF2a phosphorylation causing an increase in BACE levels also come timely [see ARF related Keystone story]. It would be interesting to find mechanisms that cause this eIF2a phosphorylation-induced switch to specific translation. Since cellular stress regulates miRNA levels, it would be interesting to see if there is some stress-miRNA-BACE connection here. It would also be fascinating to see how aging, inflammation, or other factors that influence the risk for LOAD also influence the downregulation of these miRNAs.

View all comments by Lawrence Rajendran

The role of miRNAs in fundamental biology and more recently in neurodegenerative disorders is gaining popularity (1). Now, Peter Nelson’s group provides the first evidence that changes in miRNA expression could contribute to Alzheimer disease development. These observations add to the recently published work on miRNAs in Parkinson disease (2).

Here, the authors performed miRNA microarray profiling and found miR-107 (and perhaps miR-103, which belongs to the same family) to be specifically decreased in “pre”-AD patients. For those who are not fully aware of miRNA literature, a decrease in miRNA levels would theoretically lead to increased protein expression. Interestingly, one of the candidate target genes for miR-107/103 is BACE1, and the authors show that, in vitro at least, miR-107 can indeed regulate BACE1 expression. While a follow-up study is now needed in a larger cohort of patients, these results support the hypothesis that changes in miRNA expression could be involved (perhaps early on) in sporadic AD development and that BACE1 can be regulated by miRNAs.

Overall,...  Read more

The role of miRNAs in fundamental biology and more recently in neurodegenerative disorders is gaining popularity (1). Now, Peter Nelson’s group provides the first evidence that changes in miRNA expression could contribute to Alzheimer disease development. These observations add to the recently published work on miRNAs in Parkinson disease (2).

Here, the authors performed miRNA microarray profiling and found miR-107 (and perhaps miR-103, which belongs to the same family) to be specifically decreased in “pre”-AD patients. For those who are not fully aware of miRNA literature, a decrease in miRNA levels would theoretically lead to increased protein expression. Interestingly, one of the candidate target genes for miR-107/103 is BACE1, and the authors show that, in vitro at least, miR-107 can indeed regulate BACE1 expression. While a follow-up study is now needed in a larger cohort of patients, these results support the hypothesis that changes in miRNA expression could be involved (perhaps early on) in sporadic AD development and that BACE1 can be regulated by miRNAs.

Overall, these results are in line with our own observations that we presented last year at the centennial meeting on AD in Tübingen, Germany, and the AD/PD conference in Salzburg, Austria. Now that an independent group has demonstrated similar findings, hopefully our work will soon be accepted for publication.

References:
1. Hébert SS, De Strooper B. Molecular biology. miRNAs in neurodegeneration. Science. 2007 Aug 31;317(5842):1179-80. Abstract

2. Kim J, Inoue K, Ishii J, Vanti WB, Voronov SV, Murchison E, Hannon G, Abeliovich A. A MicroRNA feedback circuit in midbrain dopamine neurons. Science. 2007 Aug 31;317(5842):1220-4. Abstract

View all comments by Sebastien S. Hebert

The Olson group is a pioneer in the field of microRNA function in muscle cells. Here, the authors provide compelling evidence that miR-206, a skeletal muscle-specific “myomiR,” functions in a complex regulatory pathway to regulate ALS pathology in mice. The strength of this paper relies on the use of different mouse models, including miR-206 knockouts, to characterize the signaling pathway in vivo.

To obtain insights into the mechanism(s) involved in muscle degeneration in ALS, the authors performed a microRNA array from ALS mice, which harbor the familial SOD1 G93A mutation. MiR-206 was the most significantly changed (upregulated) miRNA in this screen. It is interesting to note that other myomiRs, including miR-1, miR-133b, and miR-133a were, albeit at weaker levels, downregulated in the array; however, the authors could confirm by quantitative PCR the upregulation of miR-206 and miR-133b (which are co-expressed from the same transcript) in the diseased mice. MiR-206 upregulation coincided with denervation and ALS pathology in the mutant mice. To make a long story short, the...  Read more

The Olson group is a pioneer in the field of microRNA function in muscle cells. Here, the authors provide compelling evidence that miR-206, a skeletal muscle-specific “myomiR,” functions in a complex regulatory pathway to regulate ALS pathology in mice. The strength of this paper relies on the use of different mouse models, including miR-206 knockouts, to characterize the signaling pathway in vivo.

To obtain insights into the mechanism(s) involved in muscle degeneration in ALS, the authors performed a microRNA array from ALS mice, which harbor the familial SOD1 G93A mutation. MiR-206 was the most significantly changed (upregulated) miRNA in this screen. It is interesting to note that other myomiRs, including miR-1, miR-133b, and miR-133a were, albeit at weaker levels, downregulated in the array; however, the authors could confirm by quantitative PCR the upregulation of miR-206 and miR-133b (which are co-expressed from the same transcript) in the diseased mice. MiR-206 upregulation coincided with denervation and ALS pathology in the mutant mice. To make a long story short, the group identified both upstream (MyoD) and downstream (HDAC4, FGFBP1) effectors of the miR-206 network in vivo. Overall, an elegant study!

This work contributes significantly to our knowledge with regard to microRNA function in health and disease. Although individual microRNAs can target up to several hundred genes, it’s important to keep in mind that the observed pathological effects in vivo often result from the abnormal fine-tuning of a limited number of "key" genes. With regard to the current study, the effects of miR-206 in reinnervation could be explained, in most part, by the misregulation of HDAC4 (a miR-206 target). One could hypothesize that this mode of “targeted” pathological regulation could function in Alzheimer disease brain, where, for instance, miR-29 could contribute to plaque load by modulating BACE1 regulation.

Although well structured, this study does not, in my opinion, address the primary cause of motor neuron degeneration in ALS (mice or humans). An interesting follow-up study would be to look for changes in microRNA expression in the CNS. In this sense, this study lacks validation of microRNA (and target gene) expression in humans. Notably, the miR-206/miR-133b locus was originally described as a synapse-associated non-coding RNA (7H4)(see current study). Interestingly, it has been documented that miR-206 can become overexpressed in the brain after cellular insult (Jeyaseelan et al., 2008; Zhang and Pan, 2009). Also, one study associates miR-206 with schizophrenia (Hansen et al., 2007). In the current study, axonal regeneration seemed unaffected in the miR-206 knockout mice. Clearly, future studies are needed to elucidate the role of microRNAs, particularly miR-206, in both neuronal and muscle loss.

References:
Hansen T, Olsen L, Lindow M, Jakobsen KD, Ullum H, Jonsson E, Andreassen OA, Djurovic S, Melle I, Agartz I, Hall H, Timm S, Wang AG, Werge T (2007) Brain expressed microRNAs implicated in schizophrenia etiology. PLoS ONE 2:e873. Abstract

Jeyaseelan K, Lim KY, Armugam A (2008) MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke 39:959-966. Abstract

Zhang B, Pan X (2009) RDX induces aberrant expression of microRNAs in mouse brain and liver. Environ Health Perspect 117:231-240. Abstract

View all comments by Sebastien S. Hebert