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

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.

Stress granules sequester Alzheimer’s disease-associated gene transcripts and regulate disease-related neuronal proteostasis

“…We further explored the different distributions of major AD risk factors, including APP , microtubule-associated protein tau ( MAPT ) and presenilin1 ( PSEN1 ) [ 1 , 2 , 44 , 45 ], in SGs, and found that APP and ADAM metallopeptidase domain 10 ( ADAM10 ) [ 46 ] were enriched in SGs and exhibited both G3BP1 and G3BP2 eCLIP-peaks ( Supplementary Figure 3T ). The expression level of MAPT was decreased upon depletion of G3BP1 and G3BP2 and treatment with AS, suggesting that G3BP proteins and SGs assembly are likely to prevent the MAPT transcript from mRNA degradation.…”

Role of RNA binding proteins of the Drosophila behavior and human splicing (DBHS) family in health and cancer

“…SFPQ has also been shown to posttranscriptionally upregulate the expression level of amyloid-β precursor protein ( APP ), a representative gene related to Alzheimer’s disease (AD), in neural cells [ 47 , 48 ].…”

Role of piRNA biogenesis and its neuronal function in the development of neurodegenerative diseases

“…AD is the most common form of progressive dementia and is characterized by memory impairment and cognitive decline ( Masters et al, 2015 ; Knopman et al, 2021 ; Sato et al, 2021 ). Patients with AD exhibit some pathological symptoms, including amyloid plaques, which are mainly composed of aggregates of amyloid beta (Aβ) peptides, and neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau filaments that are further linked with neurodegenerative tauopathies and synaptic loss in the brain ( McKhann et al, 1984 ; Braak and Braak, 1990 , 1991 , 1996 ; Serrano-Pozo et al, 2011 ; DeTure and Dickson, 2019 ).…”