Furthermore, it was demonstrated via retrospective questionnaire-

Furthermore, it was demonstrated via retrospective questionnaire-based epidemiology that those patients who are more passive (thus less active) have an earlier age of HD onset [39]. This therefore provides a striking example of a discovery in an animal model that has led directly see more to successful studies in patients, strongly supporting the validity of these mouse models of HD and the clinical relevance of such environmental manipulations in preclinical models.

Various experimental approaches have been taken to establish how EE might be of benefit to animal models of HD, with implications for understanding how the disease might be delayed or brain repair strategies implemented. The original study revealed that EE of R6/1 XL184 HD mice from 4 weeks of age (weaning) delayed onset of motor deficits and ameliorated the loss of cerebral

volume surrounding the striatum [8]. Subsequently, it was demonstrated that this therapeutic effect of EE in R6/1 HD mice was associated with amelioration of molecular deficits involving brain-derived neurotrophic factor (BDNF) and, to a lesser extent, dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) [40,41]. Further beneficial effects in R6/1 HD mice have been demonstrated on cannabinoid CB1 receptor [42], post-synaptic density protein 95 kDa (PSD-95) [36], serotonergic system deficits [10,43] and hippocampal neurogenesis [44], neuronal morphology and dendritic spines [45,46]. Furthermore, recent findings demonstrate that EE can

even correct adrenal dysfunction in HD mice, suggesting previously unsuspected peripheral effects of EE [47]. Subsequent studies have demonstrated that increased voluntary physical exercise (wheel running) also has beneficial effects in R6/1 HD mice [48–50], although the effects observed are less 17-DMAG (Alvespimycin) HCl dramatic than those reported for EE. This has been replicated in the R6/1 mice [51] and, using the rotarod for motor training, in the R6/2 HD mice [52], although the adult hippocampal neurogenesis deficit in these mice was not rescued by access to running wheels [53]. The only study not to show beneficial behavioural effects of exercise in an animal model of HD involved the N171-81Q mice [54], in which expression of the N-terminal huntingtin protein fragment is driven by a prion promoter. Alzheimer’s disease (AD) is the most common form of dementia and involves neurodegeneration that results from both genetic and environmental factors. AD can be classified into sporadic and familial forms, based on heritability. Familial AD is usually associated with high penetrance of a single gene mutation, notably in the genes encoding amyloid precursor protein and presenilins, and early age of onset [55]. The genetics of sporadic (late onset) AD, by far the most common form, appears to be complex and polygenic, with polymorphisms in apolipoprotein E (ApoE) and many other genes implicated in disease risk.

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