Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid-β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above-mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players-mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease.
Highlights
This review summarizes the state-of-the-art understanding of and research into the Alzheimer’s disease (AD) players working as regulators of transcription and their potential contribution to AD pathogenesis
CREB depletion, these findings provide a deeper understanding of the involvement of tau in AD pathogenesis
Kinase 7 (MKK7), leading to the phosphorylation of the MAP kinase Extracellular SignalRelated Kinase 1/2 (ERK1/2). Such a signaling cascade results in the stimulation of c-Fos phosphorylation and in the consequent AP-1-dependent amyloid precursor protein (APP) transcription, which triggers an increment in Aβ production, with an efficacy increasing from APOE ε2 to APOE ε3 to Apolipoprotein E ε4 (APOE ε4) [135]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. More than 200 mutations in the genes coding for PS and about 20 in APP genes cause familiar cases of AD in an autosomal dominant manner Such mutations are localized in Aβ sequences, close to the secretase cleavage sites, and affect the enzyme-substrate complex, leading to an increase in Aβ or to an increase in the Aβ42/Aβ40 ratio [14]. These mutations in APP or PS have been exploited to generate animal models of the disease [35,36].
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