Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA.

Kaoru Sato,Makoto Hashimoto,Ken-Ichi Takayama,Satoshi Inoue

doi:10.3389/fragi.2021.721579

Abstract

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 APP gene caused by chromosomal duplication in patients with Down syndrome can promote AD pathogenesis, indicating the pathological involvement of the APP gene dose in AD. Furthermore, increased APP expression due to locus duplication and promoter mutation of APP has been found in familial AD. Given this background, we aimed to summarize the mechanism underlying the upregulation of APP expression levels from a cutting-edge perspective. We first reviewed the literature relevant to this issue, specifically focusing on the transcriptional regulation of APP by transcription factors that bind to the promoter/enhancer regions. APP expression is also regulated by growth factors, cytokines, and hormone, such as androgen. We further evaluated the possible involvement of post-transcriptional regulators of APP in AD pathogenesis, such as RNA splicing factors. Indeed, alternative splicing isoforms of APP are proposed to be involved in the increased production of Aβ. Moreover, non-coding RNAs, including microRNAs, post-transcriptionally regulate the APP expression. Collectively, elucidation of the novel mechanisms underlying the upregulation of APP would lead to the development of clinical diagnosis and treatment of AD.

Highlights

Alzheimer’s disease (AD) is the most common form of age-related dementia and a complex neurodegenerative disorder, phenotypically featured with progressive impairment of memory, thinking, and behavior as along with cognitive decline (Bateman et al, 2012; Mucke and Selkoe, 2012; Kirova et al, 2015; Hashimoto et al, 2018)
Senile plaques are mainly composed of soluble amyloid-β (Aβ) peptides (Panza et al, 2019), which form aberrant aggregates exhibiting neurotoxicity in the brain; the crucial role in the AD pathogenesis is assumed to be played by misfolded Aβ, namely amyloid
We have reviewed the cis-regulatory elements of the Aβ precursor protein (APP) transcript and trans-acting factors for the post-transcriptional regulation of APP

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of age-related dementia and a complex neurodegenerative disorder, phenotypically featured with progressive impairment of memory, thinking, and behavior as along with cognitive decline (Bateman et al, 2012; Mucke and Selkoe, 2012; Kirova et al, 2015; Hashimoto et al, 2018). Senile plaques are mainly composed of soluble amyloid-β (Aβ) peptides (Panza et al, 2019), which form aberrant aggregates exhibiting neurotoxicity in the brain; the crucial role in the AD pathogenesis is assumed to be played by misfolded Aβ, namely amyloid. In addition to the amyloidogenic pathway, the majority of APP undergoes non-pathogenic processing mediated by sequential cleavage of α-secretase and γ-secretase (Nguyen, 2019). In this pathway, an N-terminal secreted form of APP (sAPPα) is generated that plays numerous roles in normal physiological functions in the brain, such as neuronal proliferation, differentiation, migration, and synaptic function (Nguyen, 2019; Dar and Glazner, 2020)

Objectives

Conclusion