Non-coding RNAs are once again brought to the attention of the AD field. Now, intriguing work by Faghihi and coworkers reveal an unexpected role for antisense RNA transcripts (transcripts from the opposite strand to the protein-coding, or sense, strand) in the regulation of BACE1 transcription.

Interestingly, a large proportion of the genome can produce transcripts from both strands. Antisense transcripts are usually involved in the degradation of the corresponding sense transcripts (by RNA interference). Here, on the contrary, the BACE1 antisense transcript seems to positively regulate the stability of BACE1 mRNA.

Using loss- and gain-of-function experiments, the authors nicely show that BACE1 antisense transcripts follow BACE1 mRNA (sense) levels. Thus, overexpression of BACE1 antisense transcripts leads to increased BACE1 mRNA (and protein levels) with the consequence of increased activity and Aβ production, at least in HEK293-APPSw cells. Some of these observations were confirmed in vivo in the brain of wild-type mice treated with siRNAs targeted to the BACE1...  Read more

Non-coding RNAs are once again brought to the attention of the AD field. Now, intriguing work by Faghihi and coworkers reveal an unexpected role for antisense RNA transcripts (transcripts from the opposite strand to the protein-coding, or sense, strand) in the regulation of BACE1 transcription.

Interestingly, a large proportion of the genome can produce transcripts from both strands. Antisense transcripts are usually involved in the degradation of the corresponding sense transcripts (by RNA interference). Here, on the contrary, the BACE1 antisense transcript seems to positively regulate the stability of BACE1 mRNA.

Using loss- and gain-of-function experiments, the authors nicely show that BACE1 antisense transcripts follow BACE1 mRNA (sense) levels. Thus, overexpression of BACE1 antisense transcripts leads to increased BACE1 mRNA (and protein levels) with the consequence of increased activity and Aβ production, at least in HEK293-APPSw cells. Some of these observations were confirmed in vivo in the brain of wild-type mice treated with siRNAs targeted to the BACE1 antisense transcript. No functional effects were documented in these mice.

How do these findings help to understand increased BACE1 expression in sporadic patients? Several groups, including ours (Hébert et al., 2008), have confirmed increased BACE1 protein expression in a subgroup (about 30 percent of cases) of sporadic AD cases. Our work showed that this was correlated with a loss of microRNA expression, and fits with the hypothesis that a loss-of-function mechanism associated with aging could explain the increase in BACE1 protein.

The current work shows that BACE1 antisense and mRNA transcripts are significantly elevated in sporadic AD brain, and suggests a feed-forward mechanism, with Aβ inducing more antisense BACE1 transcripts and, therefore, increasing BACE1 mRNA. This adds to the current debate in the field as to whether BACE1 mRNA levels are changed or not in diseased brain [discussed in (Rossner et al., 2006) and reviewed by us (Hébert et al.)]. Interestingly, the increase in BACE1 antisense transcripts could also be observed in cells treated with exogenous Aβ42 and in the AD Tg19959 mouse model with high Aβ levels, thus supporting the “feed-forward” mechanism for the regulation of BACE1/β-secretase. Unfortunately, the authors do not provide protein data for BACE1 in the AD mouse model and patients.

Overall, this paper provides increasing support for the role of non-coding RNAs in the development of AD and possibly other neurodegenerative disease.

References:
Rossner S, Sastre M, Bourne K, Lichtenthaler SF. Transcriptional and translational regulation of BACE1 expression--implications for Alzheimer's disease. Prog Neurobiol. 2006 Jun;79(2):95-111. Abstract

Hébert SS, Horré K, Nicolaï L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, Kauppinen S, Delacourte A, De Strooper B. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6415-20. Abstract

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