Swedish mutation within amyloid precursor protein modulates global gene expression towards the pathogenesis of Alzheimer's disease

Abstract

The Swedish mutation (K595N/M596L) of amyloid precursor protein (APP-swe) has been known to increase abnormal cleavage of cellular APP by Beta-secretase (BACE), which causes tau protein hyperphosphorylation and early-onset Alzheimer's disease (AD). Here, we analyzed the effect of APP-swe in global gene expression using deep transcriptome sequencing technique. We found 283 genes were down-regulated and 348 genes were up-regulated in APP-swe expressing H4-swe cells compared to H4 wild-type cells from a total of approximately 74 million reads of 38 base pairs from each transcriptome. Two independent mechanisms such as kinase and phosphatase signaling cascades leading hyperphosphorylation of tau protein were regulated by the expression of APP-swe. Expressions of catalytic subunit as well as several regulatory subunits of protein phosphatases 2A were decreased. In contrast, expressions of tau-phosphorylating glycogen synthase kinase 3ß (GSK-3ß), cyclin dependent kinase 5 (CDK5), and cAMP-dependent protein kinase A (PKA) catalytic subunit were increased. Moreover, the expression of AD-related Aquaporin 1 and presenilin 2 expression was regulated by APP-swe. Taken together, we propose that the expression of APP-swe modulates global gene expression directed to AD pathogenesis.

Stress Conditions Increase Vimentin Cleavage by Omi/HtrA2 Protease in Human Primary Neurons and Differentiated Neuroblastoma Cells

“…In a proteomic-wide study using human Jurkat T lymphocytes, cytoskeletal proteins including vimentin were found as prime targets of Omi/HtrA2 protease [36]. Several studies have also suggested that vimentin in response to certain apoptosis stimuli is cleaved by multiple caspases, resulting in diverse vimentin fragments [43].…”

“…4e, lane 1). These are most likely due to stress-related conditions caused by overexpression of APP mutation that eventually lead to increased degradation of vimentin or affect gene expression and genes related to signal pathways involved in degradation of cytoskeleton proteins [36] (Fig. 4e, lane 1).…”

“…A systematic proteome-wide degradomics approach identified several Omi/HtrA2 substrates of potential physiological relevance, including vimentin [36]. In order to confirm whether vimentin is directly cleaved by Omi/HtrA2, recombinant Omi/ HtrA2 (134-458) was incubated with human recombinant vimentin and with β-casein as a control substrate for Omi/ HtrA2 [33].…”

Amyloid Beta-Mediated Epigenetic Alteration of Insulin-Like Growth Factor Binding Protein 3 Controls Cell Survival in Alzheimer's Disease

“…Cells expressing Swedish mutant APP have dramatic increases (up to 6- to 8-fold) in Aβ 1 – 40 and Aβ 1 – 42 production via elevated endoproteolytic cleavage at the β-secretase site [4], [5]. Our previous study also found global alterations in gene expression, including genes associated with AD pathogenesis in APP -Swedish mutant cells [6]. Insulin-like growth factor binding protein-3 ( IGFBP3 ) was one gene whose expression was significantly down-regulated in APP-Swedish mutant cells.…”

“…H4 and H4-sw cells were cultured as previously described in Dulbecco's modified Eagle media (DMEM; Gibco/BRL) containing 10% fetal bovine serum (FBS; Gibco/BRL), 100 U/mL penicillin (Gibco/BRL), 100 µg/mL streptomycin (Gibco/BRL), and 2 mM L-glutamine (Gibco/BRL) [6]. To maintain H4-sw cells, 500 µg/mL geneticin (Gibco/BRL) was added to the growth media.…”