Knockdown of BACE1-AS Nonprotein-Coding Transcript Modulates Beta-Amyloid-Related Hippocampal Neurogenesis

Abstract

Background. Alzheimer's disease (AD) is a devastating neurological disorder and the main cause of dementia in the elderly population worldwide. Adult neurogenesis appears to be upregulated very early in AD pathogenesis in response to some specific aggregates of beta-amyloid (Aβ) peptides, exhausting the neuronal stem cell pools in the brain. Previously, we characterized a conserved nonprotein-coding antisense transcript for β-secretase-1 (BACE1), a critical enzyme in AD pathophysiology. We showed that the BACE1-antisense transcript (BACE1-AS) is markedly upregulated in brain samples from AD patients and promotes the stability of the (sense) BACE1 transcript. In the current paper, we examine the relationship between BACE1, BACE1-AS, adult neurogenesis markers, and amyloid plaque formation in amyloid precursor protein (APP) transgenic mice (Tg-19959) of various ages. Results. Consistent with previous publications in other APP overexpressing mouse models, we found adult neurogenesis markers to be noticeably upregulated in Tg-19959 mice very early in the development of the disease. Knockdown of either one of BACE1 or BACE1-AS transcripts by continuous infusion of locked nucleic acid- (LNA-) modified siRNAs into the third ventricle over the period of two weeks caused concordant downregulation of both transcripts in Tg-19959 mice. Downregulation of BACE1 mRNA was followed by reduction of BACE1 protein and insoluble Aβ. Modulation of BACE1 and BACE1-AS transcripts also altered oligomeric Aβ aggregation pattern, which was in turn associated with an increase in neurogenesis markers at the RNA and protein level. Conclusion. We found alterations in the RNA and protein concentrations of several adult neurogenesis markers, as well as non-protein-coding BACE1-AS transcripts, in parallel with the course of β-amyloid synthesis and aggregation in the brain of Tg15999 mice. In addition, by knocking down BACE1 or BACE1-AS (thereby reducing Aβ production and plaque deposition), we were able to modulate expression of these neurogenesis markers. Our findings suggest a distortion of adult neurogenesis that is associated with Aβ production very early in amyloid pathogenesis. We believe that these alterations, at the molecular level, could prove useful as novel therapeutic targets and/or as early biomarkers of AD.

Promoter-associated RNAs and promoter-targeted RNAs

“…Chu et al [58] demonstrated that antisense paRNAs are needed for both activation and repression of PR transcription. Their findings were consistent with studies from Modarresi et al [59] and Hawkins et al [60]. They showed that the antisense transcript of BACE1 and Oct-4 genes played important roles in epigenetically regulating BACE1 and Oct-4 transcription, respectively.…”

The Long Non-Coding RNAs in Neurodegenerative Diseases: Novel Mechanisms of Pathogenesis

“…HuD can also bind and stabilize APP mRNA, thereby promoting Aβ42 peptide formation by increasing APP and BACE1 protein content as well as BACE1-AS lncRNA level [56]. This was observed both in cortical tissue from AD individuals and in transgenic mice over- [57]. This potential therapeutic strategy targeting BACE1 and BACE1-AS was also confirmed in a human neuroblastoma disease cell model where gene-silencing of BACE1-AS decreased the BACE1-dependent cleavage of APP with a consequent reduction of senile plaque formation [58].…”

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

“…BACE1, a core promoter of APP cleavage leading to the formation of Aβ aggregates, is abnormally activated in AD-affected brain cells due to regulation by its antisense RNA called BACE1-AS. Depleting this lncRNA in rodent models leads to a reduction in Aβ and its plaques thereby improving memory capacity in AD mouse models [293, 294]. Another dysregulated lncRNA found to closely associate with AD is brain cytoplasmic RNA 1 (BCYRN1).…”