| Summary: | Education and cognitive occupations is commonly associated to reduced risk of Alzheimer¿s disease (AD) dementia. Animal studies have demonstrated that cognitive stimulation (CS) achieved by social/physical activities and/or enriched environments compensates for memory decline. We have elaborated a novel paradigm of CS that is devoid of physical/social activity and enriched environments. 4 months-old Tg2576 mice were cognitively trained for 8 weeks and, after a break of 8 months, long-lasting effects of CS on cognitive abilities and AD-like pathology were measured. MWM and NOR tests showed that deficits in spatial and recognition memories were compensated by CS. These outcomes were accompanied by increased levels of hippocampal post-synaptic markers (PSD95 and NR1) and proteins involved in synaptic formation (Arc, â-catenin). CS softened amyloid pathology in terms of reduced levels of Aâ1-42 and the dodecameric assembly, referred as Aâ*56. CS appeared to affect the APP processing since differences in levels of ADAM17, BACE1 and C99/C83 ratio were found. Tau hyper-phosphorylation and high activities of Tau kinases were also reduced by CS. In contrast, CS did not induce any of these molecular changes in wild-type mice. The present findings suggest beneficial and long-lasting effects of CS early in life on cognitive decline and AD-like pathology. In this research work we have also characterized the role of BDNF on a new mechanism by which cognitive stimulation exerts its beneficial effects on cognitive decline and AD-like pathology.
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