Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein APP MRNA

Alzheimer's disease (AD) is an age-associated neurodegenerative disorder characterized by progressive impairment of memory, thinking, behavior, and dementia. Based on ample evidence showing neurotoxicity of amyloid-β (Aβ) aggregates in AD, proteolytically derived from amyloid precursor protein (APP), it has been assumed that misfolding of Aβ plays a crucial role in the AD pathogenesis. Additionally, extra copies of the gene caused by chromosomal duplication in patients with Down syndrome can promote AD pathogenesis, indicating the pathological involvement of the gene dose in AD. Furthermore, increased expression due to locus duplication and promoter mutation of has been found in familial AD. Given this background, we aimed to summarize the mechanism underlying the upregulation of expression levels from a cutting-edge perspective. We first reviewed the literature relevant to this issue, specifically focusing on the transcriptional regulation of by transcription factors that bind to the promoter/enhancer regions. expression is also regulated by growth factors, cytokines, and hormone, such as androgen. We further evaluated the possible involvement of post-transcriptional regulators of in AD pathogenesis, such as RNA splicing factors. Indeed, alternative splicing isoforms of are proposed to be involved in the increased production of Aβ. Moreover, non-coding RNAs, including microRNAs, post-transcriptionally regulate the expression. Collectively, elucidation of the novel mechanisms underlying the upregulation of would lead to the development of clinical diagnosis and treatment of AD.