Neuronal numbers in the frontal cortex of a novel transgenic mouse model of Alzheimer's Disease

Abstract

Alzheimer’s Disease (AD) is neurodegenerative disorder, characterized by extracellular plaques, intracellular tangles and synaptic and neuronal loss in selective brain regions. In the present study, we investigated the frontal cortex of APP/PS1 KI mice, a novel transgenic mouse model of AD. The APP/PS1 KI mice overexpress human amyloid precursor protein (APP) with the Swedish and London mutations and carry M233T/L235P knocked-in mutations in presenilin 1 (PS1). This model has shown in a previous study a substantial neuron loss in the CA1/2 pyramidal cell layer that correlated more with intraneuronal Aβ and Thioflavine S-positive aggregates than with extracellular Aβ deposits. In this study, the volume and the neuron numbers of the frontal cortex in APP/PS1 KI mice were assessed using design-based stereology. In the frontal cortex of APP/PS1 KI mice, a neuron loss of 28% was detected in layers V-VI at 10 months of age. In addition, the plaque load in these mice in layers V-VI was 11%. Thus, the amount of plaques present in the frontal cortex of these animals does not fully account for the extent of observed neuron loss. As a possible key mediator in this mechanism, the intraneuronal accumulation of Aβ is proposed. Using an Aβ and Thioflavine S double staining, intraneuronal Aβ and Thioflavine S-positive deposits were observed in layers V-VI pyramidal neurons. The APP/PS1 KI mice are concluded to be a excellent model for investigating the pathology in AD, with a substantial neuron loss in different brain regions and modelling the critical role of intraneuronal Aβ in neuron loss. Therefore, this model is an excellent tool for further research about the pathogenesis of AD and possibly testing potential therapeutics.