High-throughput efforts by us and others have provided strong evidence that, in sharp contrast to earlier understanding, much of the mammalian genome is transcribed into noncoding RNA. We now seek to understand if noncoding RNA regulatory networks may relate to the 2-amyloid hypothesis in Alzheimer's disease (AD). This application focuses on a noncoding RNA network that appears to regulate the expression of ?-secretase-1 (BACE1), a critical enzyme in AD pathophysiology and a prime AD drug target. We have recently reported that a BACE1 noncoding antisense transcript (BACE1-AS) concordantly and potently regulates BACE1 mRNA and protein expression. Important, BACE1-AS concentrations were markedly elevated in human AD patients as well as in amyloid precursor protein transgenic mice, an AD animal model. BACE1-AS is enriched in the cell nucleus but upon exposure to amyloid-? 1-42 (A? 1-42), or other cellular stressors, this noncoding transcript translocates into the cytoplasm resulting in increased BACE1 mRNA stability, as well as """"""""masking"""""""" of a microRNA binding site on BACE1 mRNA;these appear to be synergistic mechanisms leading to generation of additional A? 1-42 in a """"""""vicious cycle"""""""". This putative feed-forward pathway, linked to the release of BACE1-AS from a nuclear reservoir, may be driving aspects of AD related pathologies. Considering these findings, the present research application focuses on three aims.
Our first aim i s to gain a detailed mechanistic understanding of the in vitro regulatory effect that BACE1-AS exerts on BACE1 expression as well as the potential impact of BACE1-AS on AD related pathologies. Second, we will seek to verify that the in vitro regulatory effects of BACE1-AS on BACE1 expression are also present in vivo in mouse brain. Here we will develop BACE1-AS transgenic mice to determine if the overexpression of this noncoding RNA is sufficient to cause or accelerate AD- like pathology. Third, we will address the issue as to whether BACE1-related transcripts, notably BACE1-AS, may be useful as biomarkers for studies on AD. To complement our studies on AD and control brain samples, we shall investigate, in a large number of peripheral blood mononuclear cell samples, whether peripheral BACE1-related biomarkers might be useful as biomarkers. Overall, these experiments promise to yield significant insights into mechanisms by which BACE1 expression is controlled. Furthermore we argue that noncoding regulatory RNAs, notably BACE1-AS, must be viewed as candidates for an early biomarker signature in AD.

Public Health Relevance

Alzheimer's disease (AD) is a devastating age-related neurodegenerative disorder characterized by progressive impairment of cognition and short- term memory loss. Although controversy still exists in the link between amyloid pathway and AD and in the precedence of events leading to AD, deposition of A2 1-42 into senile plaques is a proven feature of AD neuropathology. BACE1 is a ?-site amyloid precursor protein (APP) cleaving enzyme essential for A2 1-42 biosynthesis. BACE1 is therefore a hotly pursued drug target in AD. Understanding the mechanisms by which BACE1 is regulated may reveal important insights into the pathogenesis of AD, and lead to the development of novel therapeutics and AD biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS063974-03
Application #
8029496
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Corriveau, Roderick A
Project Start
2009-02-01
Project End
2011-02-28
Budget Start
2011-02-01
Budget End
2011-02-28
Support Year
3
Fiscal Year
2011
Total Cost
$91,714
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Khorkova, Olga; Wahlestedt, Claes (2017) Oligonucleotide therapies for disorders of the nervous system. Nat Biotechnol 35:249-263
Khorkova, O; Hsiao, J; Wahlestedt, C (2015) Basic biology and therapeutic implications of lncRNA. Adv Drug Deliv Rev 87:15-24
Zeier, Zane; Esanov, Rustam; Belle, Kinsley C et al. (2015) Bromodomain inhibitors regulate the C9ORF72 locus in ALS. Exp Neurol 271:241-50
Yamanaka, Yasunari; Faghihi, Mohammad Ali; Magistri, Marco et al. (2015) Antisense RNA controls LRP1 Sense transcript expression through interaction with a chromatin-associated protein, HMGB2. Cell Rep 11:967-976
St Laurent, Georges; Wahlestedt, Claes; Kapranov, Philipp (2015) The Landscape of long noncoding RNA classification. Trends Genet 31:239-51
Khorkova, Olga; Myers, Amanda J; Hsiao, Jane et al. (2014) Natural antisense transcripts. Hum Mol Genet 23:R54-63
Halley, Paul; Kadakkuzha, Beena M; Faghihi, Mohammad Ali et al. (2014) Regulation of the apolipoprotein gene cluster by a long noncoding RNA. Cell Rep 6:222-30
Halley, Paul; Khorkova, Olga; Wahlestedt, Claes (2013) Natural antisense transcripts as therapeutic targets. Drug Discov Today Ther Strateg 10:e119-e125
Pastori, Chiara; Wahlestedt, Claes (2012) Involvement of long noncoding RNAs in diseases affecting the central nervous system. RNA Biol 9:860-70
Modarresi, Farzaneh; Faghihi, Mohammad Ali; Lopez-Toledano, Miguel A et al. (2012) Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol 30:453-9

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