Quantitative analysis of neuropathological alterations in two transgenic mouse models of Alzheimer's disease

Abstract

Mouse models of Alzheimer’s Disease (AD) contribute a lot to the understanding of etiology and pathology of AD. However, the entire clinical and neuropathological pictures of familial or sporadic AD in humans cannot be fully reconstructed in any of these available models. Exhibiting pathological characteristics of AD such as amyloid deposition, neuron loss, aggregation of phosphorylated Tau and behavioural or memory deficits, mouse models reflect various aspects of the disease and therefore help us to gain a deeper insight in its pathogenesis and enable to take next steps towards developing a therapy against it. The present study aimed at further investigation of two transgenic mouse models of Alzheimer’s disease (AD): Tg4-42 and 5XFAD. Tg4-42 mice overexpress Aβ4-42 without any mutations, and develop a massive hippocampal neuron loss and severe cognitive deficits induced through intraneuronal accumulation of N-terminally truncated Aβ4-42 without amyloid plaque formation. As current drug treatments have only modest effects on the symptomatic course of Alzheimer’s disease, environmental interventions are of great interest in order to prevent AD or delay its onset. In the first part of this study using unbiased stereology it was shown that environmental enrichment, combining physical activity and cognitive enhancement, leads to an amelioration of neuronal loss in the dentate gyrus (DG) of Tg4-42 mice. Furthermore, the evidences were provided that physical activity triggers neurogenesis in the DG of Tg4-42 mice and rescues it to the wild-type levels. The results obtained in this study underline the importance of environmental enrichment, in particular increased physical activity, as a potential strategy in the prevention of dementia. The focus of the second part of this study laid on the 5XFAD mouse model, which is a widely used model, based on the expression of mutant amyloid precursor protein and presenilin-1 genes. It is a typical model for early plaque formation, intraneuronal Aβ aggregation, neuron loss and robust behavioural deficits. This project aimed at investigating the gene dosage dependence of the neuropathological features in 5XFAD. In the present study, it was shown that the levels of extracellular amyloid formations are significantly elevated in the homozygous 5XFAD groups (5XFADhom) compared to the respective hemizygous 5XFAD groups in all analysed brain regions at all points of time. Along with the aggravation of the amyloidosis, it was demonstrated that 5XFADhom mice show severe axonal degeneration in the pons and the spinal cord compared to age-matched heterozygous mice. Thereby, homozygous 5XFAD mice represent a model with several advantages comparing with the heterozygous mice: 5XFADhom mice develop amyloid pathology much more rapidly as well as a neurological phenotype. Bred to homozygosity, 5XFAD mice show a strongly reduced age of onset of neuropathological alterations. These advantages can speed up preclinical studies and reduce the number of animals used for AD research. To conclude, the results obtained in this study have broadened the knowledge about the 5XFAD and the Tg4-42 mouse models and have further validated them as appropriate models for investigation of AD.