title: Early cognitive stimulation compensates for memory and pathological changes in Tg2576 mice.
abstract: Education and cognitive occupations are commonly associated to reduce risk of Alzheimer's disease (AD) or 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 month-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. Morris Water Maze (MWM) and Novel Object Recognition (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, β-catenin). CS softened amyloid pathology in terms of reduced levels of Aβ1-42 and the dodecameric assembly, referred as Aβ*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.
authors.affiliation: Department of Pharmacology, University of Navarra, Pamplona, Spain.
authors.forename: Gorka
authors.initials: G
authors.lastname: Gerenu
authors.forename: Marta
authors.initials: M
authors.lastname: Dobarro
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ramirez
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Gil-Bea
mesh_terms: D000071443:12E7 Antigen; D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D001522:Behavior, Animal; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D003071:Cognition; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D051528:Guanylate Kinases / Q000096:biosynthesis / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis / Q000235:genetics; D018782:Maze Learning; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate; D000097802:CD83 Antigen
chemical_list: D000071443:12E7 Antigen; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015703:Antigens, CD; D016282:Aspartic Acid Endopeptidases; D015415:Biomarkers; D002352:Carrier Proteins; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D000097802:CD83 Antigen; C545487:APP protein, human; C522605:Cd99 protein, mouse; C501447:Dlg4 protein, mouse; C121673:Gprin1 protein, mouse; C075222:amyloid beta-protein (1-42); C509282:Bace1 protein, mouse; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse