Quantitative expression analysis of APP pathway and tau phosphorylation-related genes in the ICV STZ-induced non-human primate model of sporadic Alzheimer's disease.

Sang-Je Park,Youngjeon Lee,Jae-Won Huh,Sun-Uk Kim,Ji-Su Kim,Sang-Rae Lee,Young Park,Bo-Woong Sim,Kyu-Tae Chang,Se-Hee Choe,Gyu-Hwi Nam,Kyoung-Min Lee,Young-Hyun Kim,Bong-Seok Song,Kang-Jin Jeong

doi:10.3390/ijms16022386

Abstract

The accumulation and aggregation of misfolded proteins in the brain, such as amyloid-β (Aβ) and hyperphosphorylated tau, is a neuropathological hallmark of Alzheimer’s disease (AD). Previously, we developed and validated a novel non-human primate model for sporadic AD (sAD) research using intracerebroventricular administration of streptozotocin (icv STZ). To date, no characterization of AD-related genes in different brain regions has been performed. Therefore, in the current study, the expression of seven amyloid precursor protein (APP) pathway-related and five tau phosphorylation-related genes was investigated by quantitative real-time PCR experiments, using two matched-pair brain samples from control and icv STZ-treated cynomolgus monkeys. The genes showed similar expression patterns within the control and icv STZ-treated groups; however, marked differences in gene expression patterns were observed between the control and icv STZ-treated groups. Remarkably, other than β-secretase (BACE1) and cyclin-dependent kinase 5 (CDK5), all the genes tested showed similar expression patterns in AD models compared to controls, with increased levels in the precuneus and occipital cortex. However, significant changes in gene expression patterns were not detected in the frontal cortex, hippocampus, or posterior cingulate. Based on these results, we conclude that APP may be cleaved via the general metabolic mechanisms of increased α- and γ-secretase levels, and that hyperphosphorylation of tau could be mediated by elevated levels of tau protein kinase, specifically in the precuneus and occipital cortex.

Highlights

Sporadic Alzheimer’s disease is the most common neurodegenerative disease in the human population
Increased expression of ADAM17 was observed in the frontal cortex compared to the other tissues examined
These results indicate that genes of the amyloid precursor protein (APP) pathway-related group and tau phosphorylation-related group seem to be maintained at similar levels under normal conditions

Summary

Introduction

Sporadic Alzheimer’s disease (sAD) is the most common neurodegenerative disease in the human population. The majority of AD cases are sAD (≥95%), and result from neuronal loss, accumulation of senile plaques consisting of amyloid-β peptide (Aβ), aggregation of neurofibrillary tangles consisting of hyperphosphorylated tau protein, and brain atrophy [2]. Many molecular alterations were identified in sAD, including activation of pro-death genes and signaling pathways, mitochondrial dysfunction, impairment of energy metabolism, synaptic dysfunction, and oxidative and inflammatory damage [1,5]. These changes have been correlated with the accumulation of misfolded Aβ and hyperphosphorylated tau proteins in the aging brain

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Conclusion