Figure-2. Elevated antisense RNA up-regulates β-secretase-1 in Alzheimer's disease.

BACE1-AS is a non-protein-coding antisense RNA that regulates β-secretase-1 (BACE1). BACE1, a β-site amyloid precursor protein (APP)-cleaving enzyme, has been implicated in the pathogenesis of Alzheimer disease. BACE1 is involved in the production of the amyloid β (Aβ) peptides that form plaques in the brains of individuals with Alzheimer disease.

(a) BACE1-AS is enriched in the nucleus in the physiologic conditions, when neurons producing basal levels of BACE1 mRNA and protein. (b) Exposure of the neuronal cells to various cell stressors, such as reactive oxygen species, chronic hypoxia and toxic metabolites, may cause cytosolic translocation of BACE1-AS transcripts. BACE1-AS can possibly form a duplex RNA with the BACE1 mRNA, leading to stabilization of this transcript and up-regulation of BACE1 protein. BACE1 protein up-regulation, in turn can produce more Aβ peptides and drive the generation of amyloid plaques. (c) Amyloid peptides and plaques are known cellular stressors and could provoke more stress to neuronal cells and lead to over-expression and release of BACE1-AS. This later event possibly drives a feed-forward mechanism resulting in neuronal cells loss. The expression of BACE1-AS is elevated in Alzheimer's disease and induces feed-forward regulation of BACE1 ⁶. It has also been shown that BACE1-AS induces production of Aβ peptides, which leads to increased expression of BACE1, which in turn further amplifies Aβ production ⁶. Subsequently, increasing Aβ levels can further boost that BACE1-AS expression, thereby accelerating the onset of Alzheimer's disease. We suggest that therapeutic targeting of BACE1-AS could mediate the transition between the essential physiological functions of BACE1 and its pathological malfunction in early Alzheimer's disease ⁶.