Apart from the more obvious role of miRNAs in regulating the expression of disease-related genes (e.g., APP and BACE1), it is likely that a combination of more subtle (direct or indirect) mechanisms alter disease progression over years, possibly decades. As example, sustained miR-29 deficiency may not only increase BACE1 and Aβ
levels, but also affect DNA methylation and neuronal survival [46
]. In addition, it remains difficult to predict whether the observed changes in miRNA levels in humans are a cause or consequence of the neurodegenerative process. The study of miRNA expression profiles in AD mouse models may help to address these questions.
Wang et al. were the first to study global miRNA profiles from AD mice using microarrays [48
]. For this, they used the APPSwe-PS1M146L mouse model. Of the 37 differently expressed miRNAs, several (miR-20a, miR-29a, miR-125b, miR-128a, and miR-106b) miRNAs were significantly downregulated, while others (miR-34a, let-7, miR-28, and miR-98) were upregulated. Interestingly, some miRNAs were similarly shown to be affected in AD brain in humans, including miR-29a and miR-106b [9
]. It is noteworthy that miRNA alterations were measured at 3 months of age prior to Aβ
plaque formation. In most cases, miRNA alterations were maintained or even accentuated during amyloid plaque formation at 6 months of age, therefore supporting the “cause” hypothesis. The increase in miR-34a in the mutant mice is proposed to function in regulating apoptosis via Bcl-2 modulation [48
]. In a follow-up study, the group showed by sensitive miRNA quantitative RT-PCR that miR-106b is upregulated in 3-month-old AD mice but downregulated at 6 months [50
]. These changes correlated to some extent with transforming growth factor, beta receptor II (Tβ
RII) expression, and a putative miR-106b target gene [50
]. While these studies highlight the importance of microarray validation, they also suggest a possible transient effect of AD pathology (in this case Aβ
plaque formation) on miRNA expression and vice versa.
More recently, Schonrock et al. studied the effects of exogenous Aβ
on miRNA expression levels in mouse hippocampal neurons in culture [51
]. Again, several miRNAs downregulated by Aβ
treatment were previously found to be decreased in human AD brain, including miR-9, miR-181c, miR-30c, miR-148b, miR-20b, and let-7i. Of interest, certain miRNAs decreased concomitantly with Aβ
pathology progression in vivo
in APP23 mice expressing human APP751 with the K670N/M671L mutations. While these observations support the “consequence” hypothesis of miRNA dysregulation in AD, it is noteworthy that some miRNA molecules became affected prior
plaque formation (like miR-409-3p and let-7i) similar to what is seen in the Wang et al. study ([48
], see above). Furthermore, the expression of certain miRNAs changed over time (from up- to downregulated or vice versa), again supporting the transient effect on miRNA expression during AD development.
While studying the role of actin and the actin-binding protein cofilin in AD, Yao et al. observed decreased miR-103 and miR-107 levels in 4-month old (Aβ
plaque bearing) Tg19959 mice that express mutant APP with KM670/671NL and V717F FAD mutations [52
]. As mentioned above, both miR-103 and miR-107 were shown to be decreased in MCI and late-onset AD [10
]. The authors further showed that these miRNA paralogues could effectively regulate cofilin expression in vitro
, providing a mechanism for the observed increase in rod-like structures in this mouse model.
Loss of presenilin function is proposed to underlie memory impairment and neurodegeneration in the pathogenesis of AD [53
]. Interestingly, small-scale miRNA profiling from Psen1 KO mice with, as a result, reduced γ
-secretase activity and Aβ
production, showed that miR-9 down-regulation coincided with neurodegeneration [54
]. It is noteworthy that miR-9 was shown to be an important regulator of neurogenesis, both in zebrafish and mice [55
]. Based on these observations, it is tempting to speculate that miR-9, which is downregulated in AD brain, participates actively in neuronal maintenance, and functions in a feedback loop with Aβ
Candidate miRNA approaches have equally been performed. For instance, Li et al. studied miR-146a expression in five different AD mouse models, including Tg-2576, Tg-CRND8, PSAPP, 3xTg-AD, and 5XFAD [57
]. This group had shown earlier that miR-146a expression levels were increased in AD brain [58
]. It turned out that miR-146a was significantly increased in age (4- to 12-month-old) when compared to young (1- to 2-month-old) mice, and this, independently of the model tested [57
]. Notably, miR-146a has repeatedly been shown to be implicated in the regulation of the inflammatory response [59
]. Moreover, neuroinflammation is thought to play a critical role in the pathogenesis of chronic neurodegenerative diseases including AD [60
], evoking the hypothesis that miR-146a overexpression in these AD models could reflect a defense mechanism against the deleterious effects of neuroinflammation. Interestingly, synthetic Aβ
was shown to induce miR-146a expression in cultured human neuronal (and glial) cells [58
]. Taken together, the abovementioned observations suggest that miRNA-regulated gene pathways, such as the miR-146a pathway, could function both upstream and downstream of AD pathology (cause and consequence).