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
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)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
