Studies on APP metabolism related to age-associated mitochondrial dysfunction in APP/PS1 transgenic mice.

Lizhi Chen,Tong Wu,Shicheng Xu,Hai Tang,Lingqi Zhou,Yijia Shao,Wenhua Huang,Shanshan Ou,Kaihua Guo,Li Luo,Jie Xu

doi:10.18632/aging.102451

Abstract

The aging brain with mitochondrial dysfunction and a reduced adenosine 5’-triphosphate (ATP) has been implicated in the onset and progression of β-Amyloid (Aβ)-induced neuronal toxicity in AD. To unravel the function of ATP and the underlying mechanisms on AD development, APP/PS1 double transgenic mice and wild-type (WT) C57 mice at 6 and 10 months of age were studied. We demonstrated a decreased ATP release in the hippocampus and platelet of APP/PS1 mice, comparing to C57 mice at a relatively early age. Levels of Aβ were raised in both hippocampus and platelet of APP/PS1 mice, accompanied by a decrease of α-secretase activity and an increase of β-secretase activity. Moreover, our results presented an age-dependent rise in mitochondrial vulnerability to oxidation in APP/PS1 mice. In addition, we found decreased pSer473-Akt levels, increased GSK3β activity by inhibiting phosphorylation at Ser9 in aged APP/PS1 mice and these dysfunctions probably due to down-regulation of Bcl-2 and up-regulation of cleaved caspase-3. Therefore, we demonstrate that PI3K/Akt/GSK3β signaling pathway could be involved in Aβ-associated mitochondrial dysfunction of APP/PS1 mice and APP abnormal metabolism in platelet might provide potential biomarkers for early diagnosis of AD.

Highlights

Alzheimer’s disease (AD) is a complicated and multifaceted neurodegenerative disease initiated by the misfolding and abnormal accumulation of intracellular and extracellular deposits [1]
Similar outcomes were acquired between hippocampal Aβ1-42 and platelet Aβ1-42 in amyloid precursor protein (APP)/PS1 mice shown in Figure 3B (r=0.856, p=0.014; r=0.882, p=0.009)
Growing researches have been focused on the precise link between the intracellular Aggregation of toxic βamyloid (Aβ) cascade and the structure/function of mitochondria as early events in AD pathogenesis [3]

Summary

INTRODUCTION

Alzheimer’s disease (AD) is a complicated and multifaceted neurodegenerative disease initiated by the misfolding and abnormal accumulation of intracellular and extracellular deposits [1]. An increasing amount of evidence has shown that mitochondria is important intracellular organelle for Aβ accumulating [3, 4] and mitochondrial dysfunctions are heavily involved in AD [5]. Previous data indicate that AD-associated proteins and peptides are localized in mitochondria, which in part characterized by a decrease of ATP, impaired oxidative www.aging-us.com phosphorylation and increased reactive oxygen species (ROS) generation [6, 7]. Mitochondria are sensitive to the irreversible loss of neuronal function and the neuronal death that cause deficits in the activities of the respiratory chain complexes and results in an increase of free radical production and a decrease of adenosine 5'-triphosphate (ATP) production [9]. We use the transgenic mice carrying APPswe/PS1dE9 mutations (APP/PS1 mice) as our AD model as they mimic critical AD symptoms such as robust Aβ accumulation and memory decline [14]

RESULTS

DISCUSSION

MATERIALS AND METHODS