Hippocampal Proteomic Analysis Reveals Distinct Pathway Deregulation Profiles at Early and Late Stages in a Rat Model of Alzheimer’s-Like Amyloid Pathology

Abstract

The cerebral accumulation and cytotoxicity of amyloid beta (Aβ) is central to Alzheimer's pathogenesis. However, little is known about how the amyloid pathology affects the global expression of brain proteins at different disease stages. In order to identify genotype and time-dependent significant changes in protein expression, we employed quantitative proteomics analysis of hippocampal tissue from the McGill-R-Thy1-APP rat model of Alzheimer-like amyloid pathology. McGill transgenic rats were compared to wild-type rats at early and late pathology stages, i.e., when intraneuronal Aβ amyloid burden is conspicuous and when extracellular amyloid plaques are abundant with more pronounced cognitive deficits. After correction for multiple testing, the expression levels of 64 proteins were found to be considerably different in transgenic versus wild-type rats at the pre-plaque stage (3 months), and 86 proteins in the post-plaque group (12 months), with only 9 differentially regulated proteins common to the 2 time-points. This minimal overlap supports the hypothesis that different molecular pathways are affected in the hippocampus at early and late stages of the amyloid pathology throughout its continuum. At early stages, disturbances in pathways related to cellular responses to stress, protein homeostasis, and neuronal structure are predominant, while disturbances in metabolic energy generation dominate at later stages. These results shed new light on the molecular pathways affected by the early accumulation of Aβ and how the evolving amyloid pathology impacts other complex metabolic pathways.

Experimental Pharmacology in Transgenic Rodent Models of Alzheimer’s Disease

“…Our laboratory has developed tg lines expressing human APP with the double Swedish and the Indiana mutations under the Thy1 promoter, which recapitulate key features of the AD-like amyloid pathology in mice and rats. The McGill-Thy1-APP mice (Ferretti et al, 2011) and McGill-R-Thy1-APP rats (Leon et al, 2010) have been extensively studied by us (Cuello et al, 2010, 2012; Ferretti et al, 2012a,b; Hanzel et al, 2014; Iulita et al, 2014, 2017; Pimentel et al, 2015; Do Carmo et al, 2016, 2018; Wilson et al, 2017a,b, 2018; Hall et al, 2018) and others (Nilsen et al, 2012, 2014a,b; Galeano et al, 2014, 2018; Qi et al, 2014, 2018; Heggland et al, 2015; Martino Adami et al, 2017a,b; Parent et al, 2017; Zhang et al, 2017; Prestia et al, 2018). In the following section, we will discuss the particular value of these specific models in experimental pharmacology.…”

Loss of Ryanodine Receptor 2 impairs neuronal activity-dependent remodeling of dendritic spines and triggers compensatory neuronal hyperexcitability

“…Furthermore, this approach opened a window of opportunity for studying putative compensatory mechanisms following RyR2 dysregulation. This was important because, apart from post-translation modifications of RyR2 [26], downregulation of RyR2 expression levels was observed in both, humans samples [28,39] and an animal model of Alzheimer's disease [38]. Following acute RyR2 deletion, we observed compensatory changes on two levels.…”

“…This approach enabled us to investigate the acute effects of RyR2 deletion on spine density gaining insight into putative compensatory mechanisms. Since altered regulation of RyR2 expression has been observed in pathological conditions such as Alzheimer's disease [28,38,39], the observation of compensatory mechanisms on the level of neuronal excitability, neuronal morphology and network function might provide important pathophysiological insights. Thus, we unilaterally injected either rAAV.…”

Vildagliptin prevents cognitive deficits and neuronal apoptosis in a rat model of Alzheimer's disease

“…It has been reported that Aβ plaques are present in the brain of approximately one-third to one-half of individuals aged ≥65, and tau inclusions are present almost universally (30). In AD, APP is cleaved by β-secretase and γ-secretase to produce toxic Aβ protein, which is involved in plaque formation (31). In the present study, vildagliptin was demonstrated to significantly reduce APP and p-tau protein expression, with this effect being more pronounced at the higher 10 mg/kg vildagliptin dose.…”