Knockdown of BACE1-AS nonprotein-coding transcript modulates beta-amyloid-related hippocampal neurogenesis

Miguel A. Lopez-Toledano, Farzaneh Modarresi, Mohammad Ali Faghihi, Nikunj S. Patel, Barbara G. Sahagan, Claes Wahlestedt

Research output: Contribution to journalArticle

96 Scopus citations

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 (A) peptides, exhausting the neuronal stem cell pools in the brain. Previously, we characterized a conserved nonprotein-coding antisense transcript for -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 A. Modulation of BACE1 and BACE1-AS transcripts also altered oligomeric A 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 -amyloid synthesis and aggregation in the brain of Tg15999 mice. In addition, by knocking down BACE1 or BACE1-AS (thereby reducing A 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 A 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.

Original languageEnglish (US)
Article number929042
JournalInternational Journal of Alzheimer's Disease
DOIs
StatePublished - 2011

ASJC Scopus subject areas

  • Aging
  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience
  • Behavioral Neuroscience

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