Presenilins Interactome in Alzheimer’s Disease and Pathological Ageing

Abstract

Alzheimer's disease (AD) is the most common type of dementia characterized by massive neuronal loss. Pathological hallmarks of the disease are overproduction of β-amyloid (Aβ) and hyperphosphorylation of tau protein accumulated into senile plaques (SPs) and neurofibrillary tangles (NFTs), respectively. SPs with cortical tau pathology are also hallmark of pathological ageing (PA). Recently, an extensive overlap has been shown between Aβ levels and profiles in PA and AD brains, suggesting that PA could be a prodromal AD phase. Presenilins are major components of the γ-secretase complex involved in Aβ production. Furthermore, presenilins interact with players of numerous signalling pathways important in the PA and AD. Integration of various modern research approaches would reinforce the role of presenilins signalling network in brain pathology. These approaches include high-throughput (epi)genetic and transcriptomic analyses, large-scale microscopic imaging studies, immunoaffinity purification or mass spectrometry. Comprehensive integration of these methods is necessary to update the definition of the role of presenilins in AD and PA. Hereby, we summarize the available data on presenilins' functions and interactions. We believe that the systematization of the existing knowledge will stimulate further research and will help reveal the molecular nooks and crannies in Alzheimer's disease and in pathological ageing.

Genome-Wide Gene-Based Multi-Trait Analysis

“…For example, gene RBM45, known as the RNAbinding motif protein 45 or developmentally regulated RNAbinding protein-1 (Drbp1), has been shown to be associated with the degenerative neurological changes in AD patients (Eck et al, 2018). Gene UPK1B has been shown to be cooperated with CD9 and CD81 and is directly involved in the pathological process of AD (De Strooper and Wakabayashi, 2011;Orre et al, 2014;Wężyk and Żekanowski, 2017). Mutation in gene TLR4 reduces microglial activation, increases Aβ deposits, and exacerbates cognitive deficits in a mouse model of AD (Song et al, 2011).…”

Characterization of the γ-secretase subunit interactome in Arabidopsis thaliana

“…The modes of substrate processing and the functions of the presenilin 1 and presenilin 2 complexes are somewhat different (Meckler and Checler 2016;Yonemura et al 2016;Stanga et al 2017). There are many known substrates of γ-secretase, including an amyloid precursor protein (APP), cadherins, interleukin receptor 1, Notch receptor, and ligands of Notch receptor (McCarthy et al 2009;Haapasalo and Kovacs 2011;Wężyk and Żekanowski 2017). In addition to their γ-secretase activity, presenilins maintain cell calcium homeostasis via an independent mechanism (Zhang et al 2010;Kuo et al 2015;Lee et al 2015).…”