Abstract
The deposition of amyloid-beta (Aβ) through the cleavage of amyloid-beta precursor protein (APP) is a biomarker of Alzheimer’s disease (AD). This study used QIAGEN Ingenuity Pathway Analysis (IPA) to conduct meta-analysis on the molecular mechanisms by which methamphetamine (METH) impacts AD through modulating the expression of APP. All the molecules affected by METH and APP were collected from the QIAGEN Knowledge Base (QKB); 78 overlapping molecules were identified. Upon simulation of METH exposure using the “Molecule Activity Predictor” feature, eight molecules were found to be affected by METH and exhibited activation relationships on APP expression at a confidence of p = 0.000453 (Z-score = 3.51, two-tailed). Core Analysis of these eight molecules identified High Mobility Group Box protein 1 (HMGB1) signaling pathway among the top 5 canonical pathways with most overlap with the 8-molecule dataset. Simulated METH exposure increased APP expression through HMGB1 at a confidence of p < 0.00001 (Z-score = 7.64, two-tailed). HMGB1 is a pathogenic hallmark in AD progression. It not only increases the production of inflammatory mediators, but also mediates the disruption of the blood-brain barrier. Our analyses suggest the involvement of HMGB1 signaling pathway in METH-induced modulation of APP as a potential casual factor of AD.
Highlights
Alzheimer’s disease (AD) is a form of dementia characterized by the accumulation of amyloid beta (Aβ) plaques, neuronal damage and loss, neurofibrillary tangles of tau protein, and neuroinflammation
Among these 78 molecules, 12 were chemical drugs and toxicants and thereby not included in further analysis in order to simulate biological systems; 28 molecules had either undetermined changes upon METH exposure or inconclusive directionality or influence on amyloid precursor protein (APP) expression, and thereby were excluded from further analysis; 30 molecules were downstream of APP and could potentially have an effect on AD progression, but their influence is not contingent upon METH exposure, and were excluded from further analysis since our study focused on the effects of METH on APP; and the remaining
Upstream of APP were further analyzed. Among these 8 molecules, JUN, MAPK3, IL6, TNF, IL1, IL1A, IL1B, and Matrix metalloproteinase-9 (MMP9) were activated by METH exposure and IGF1R was inhibited by METH exposure
Summary
Alzheimer’s disease (AD) is a form of dementia characterized by the accumulation of amyloid beta (Aβ) plaques, neuronal damage and loss, neurofibrillary tangles of tau protein, and neuroinflammation. The deposition of Aβ monomers occurs through the proteolytic cleavage of amyloid precursor protein (APP), a transmembrane protein and one of the most abundant proteins in the central nervous system (CNS) [1]. The non-amyloidogenic pathway involves cleavage of APP by the enzyme α-secretase to produce a soluble N-terminal fragment, sAPPα, and a C-terminal fragment, which is further cleaved by γ-secretase. The amyloidogenic pathway involves cleavage of APP by β-secretase to produce a soluble N-terminal fragment, sAPPβ, and a C-terminal fragment, which is further cleaved by γ-secretase to produce 40-amino-acid peptide Aβ40 and 42-amino-acid peptide. The accumulation of Aβ peptides into plaques gave rise to the “amyloid-β cascade” hypothesis that, contentious, identifies these plaques as a central pathogenic feature of AD
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