Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy

Neurodegenerative disorders referred to as tauopathies, which includes Alzheimer's disease (AD), are characterized by insoluble deposits of the tau protein within neuron cell bodies and dendritic processes in the brain. Tau is normally associated with microtubules (MTs) in axons, where it provides MT stabilization and may modulate axonal transport. However, tau becomes hyperphosphorylated and dissociates from MTs in tauopathies, with evidence of reduced MT stability and defective axonal transport. This has led to the hypothesis that MT-stabilizing drugs may have potential for the treatment of tauopathies. Prior studies demonstrated that the brain-penetrant MT-stabilizing drug, epothilone D, had salutary effects in transgenic (Tg) mouse models of tauopathy, improving MT density and axonal transport, while reducing axonal dystrophy. Moreover, epothilone D enhanced cognitive performance and decreased hippocampal neuron loss, with evidence of reduced tau pathology. To date, epothilone D has been the only non-peptide small molecule MT-stabilizing agent to be evaluated in Tg tau mice. Herein, we demonstrate the efficacy of another small molecule brain-penetrant MT-stabilizing agent, dictyostatin, in the PS19 tau Tg mouse model. Although dictyostatin was poorly tolerated at once-weekly doses of 1 mg/kg or 0.3 mg/kg, likely due to gastrointestinal (GI) complications, a dictyostatin dose of 0.1 mg/kg was better tolerated, such that the majority of 6-month old PS19 mice, which harbor a moderate level of brain tau pathology, completed a 3-month dosing study without evidence of significant body weight loss. Importantly, as previously observed with epothilone D, the dictyostatin-treated PS19 mice displayed improved MT density and reduced axonal dystrophy, with a reduction of tau pathology and a trend toward increased hippocampal neuron survival relative to vehicle-treated PS19 mice. Thus, despite evidence of dose-limiting peripheral side effects, the observed positive brain outcomes in dictyostatin-treated aged PS19 mice reinforces the concept that MT-stabilizing compounds have significant potential for the treatment of tauopathies

Gaze Direction and Request Gesture in Social Interactions

One of the most important faculties of humans is to understand the behaviour of other conspecifics. The present study aimed at determining whether, in a social context, request gesture and gaze direction of an individual are enough to infer his/her intention to communicate, by searching for their effects on the kinematics of another individual's arm action. In four experiments participants reached, grasped and lifted a bottle filled of orange juice in presence of an empty glass. In experiment 1, the further presence of a conspecific not producing any request with a hand and gaze did not modify the kinematics of the sequence. Conversely, experiments 2 and 3 showed that the presence of a conspecific producing only a request of pouring by holding the glass with his/her right hand, or only a request of comunicating with the conspecific, by using his/her gaze, affected lifting and grasping of the sequence, respectively. Experiment 4 showed that hand gesture and eye contact simultaneously produced affected the entire sequence. The results suggest that the presence of both request gesture and direct gaze produced by an individual changes the control of a motor sequence executed by another individual. We propose that a social request activates a social affordance that interferes with the control of whatever sequence and that the gaze of the potential receiver who held the glass with her hand modulates the effectiveness of the manual gesture. This paradigm if applied to individuals affected by autism disorder can give new insight on the nature of their impairment in social interaction and communication