Apathy-like syndrome associated with early lesion in the triple-transgenic 3xTgAD mouse

Abstract

Alzheimer's disease (AD) is characterized by progressive impairment of memory accompanied by several psychiatric disturbances. Apathy is one of the major neuropsychiatric manifestations in AD and is considered as the most severe symptom. Apathy is an early hallmark of the disease and consistently persists as the disease progresses. In humans, apathy can be assessed by measuring locomotor activity by ambulatory actigraphy. One of the best animal models of AD is the triple-transgenic 3xTgAD mouse harbouring PS1M146V, APPswe and tauP301L (LaFerla). These mice progressively accumulate intraneuronal Abeta, mainly in the hippocampus, amygdala and entorhinal cortex, and develop extracellular Abeta deposits and neurofibrillary tangle-like pathology in a progressive and age-dependent manner. We measured mice circadian amplitude of locomotor rhythms using a fully automatized photocell activity meter system. All animals were further examined for motor function using an accelerating rotarod task. Abeta immunohistochemistry was performed using FCA18 and 2H3 that recognizes the N-terminal free Asp residue and amino acids 1-12 of Abeta, respectively. Profound decreased locomotor activity was observed in 3xTgAD mice as early as 3 month of age as compared to non-transgenic mice. Both horizontal activity and rearing were decreased in an age-dependent manner in both males and females. After the assessment of spontaneous activity, we examined motor function with an accelerating rotarod task. The 3xTgAD mice did not show any disturbed sensorimotor function. Using FCA18 or 2H3 antibodies, we detected intracellular labeling in a specific subset of pyramidal neurons in the subiculum and CA1 of the hippocampus in mice as early as 3 month. The number of immunostained neurons was progressively increased until about 13-14 month, where after the staining became mainly extracellular. These studies show a decreased locomotor activity in the 3xTgAD mice without impairment in sensorimotor function. Therefore, altered locomotor activity most likely reflects an apathy-like phenotype of the 3xTgAD mouse, which occurs early in the pathology and progressively worsens during life-time, as observed in AD patients. Moreover our data show a perfect correlation between the kinetics of intracellular FCA18-related labeling and loss of locomotor activity and suggest a direct or indirect link of intracellular Abeta-like immunoreactivity and apathy.