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

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.

Zero Echo Time 17O-MRI Reveals Decreased Cerebral Metabolic Rate of Oxygen Consumption in a Murine Model of Amyloidosis

“…This suggests that the lower resting state CMRO 2 does not simply result from restricted access to oxygen due to limited blood flow, but rather indicates altered mitochondrial function. This is consistent with previous studies in aged APP/PS1 that have reported decreased COX and SDH activity [ 28 ], as well as lower PGC1α and Tfam protein levels [ 29 ], suggesting a mitochondrial impairment in this model. Resting state CBF might nonetheless be regionally impaired in APP swe /PS1 dE9 , which would not necessarily be captured by our analysis over 8 voxels and/or might not reach significance given our small sample size.…”

Dysregulation of thede novoproteome accompanies pathology progression in the APP/PS1 mouse model of Alzheimer’s disease

“…Mitochondrial dysfunction is known to be an early event in both APP/PS1 mice (Chen et al, 2019) and human AD brain pathology (Hauptmann et al, 2009;Moreira et al, 2007;Nunomura et al, 2001), and is believed to play a role in the synaptic loss that occurs early in the disease process (Du et al, 2012). Downregulated synthesis of mitochondrial proteins, specifically the oxidative phosphorylation-associated proteins Ndufs5, Ndufa12, Cox4i1 and Cox6b in the asymptomatic APP/PS1 mice could underlie the decreased electron transport chain capacity observed in this and other models of AD-like pathology (Bo et al, 2014;David et al, 2005).…”

Age-dependent Shift in the de Novo Proteome Accompanies Pathogenesis in an Alzheimer’s Disease Mouse Model

“…Mitochondrial dysfunction is known to be an early event in both APP/PS1 mice 58 and human AD brain pathology [59][60][61] , and is believed to play a role in the synaptic loss that occurs early in the disease process 62 . Downregulated synthesis of mitochondrial proteins, specifically the oxidative phosphorylation-associated proteins Ndufs5, Ndufa12, Cox4i1…”