title: Effects of early maternal separation on biobehavioral and neuropathological markers of Alzheimer's disease in adult male rats.
abstract: Stress has been described as a risk factor for the development of Alzheimer´s disease (AD). In the present work we aim to study the validity of an experimental model of neonatal chronic stress in order to recapitulate the main hallmarks of AD. Male Wistar rats that were separated daily from the dam during the first 3 weeks of life (maternal separation, MS) showed in adulthood cognitive deficits novel object recognition test. In the hippocampus of MS rats, increases in both Aβ40 and Aβ42 levels, the principal constituent of amyloid plaques observed in AD, were accompanied by increased expression of the cleaving enzyme BACE1. Hyperphosphorylation of Tau associated to increased activation of the tau kinase JNK1 was also found. Decreased cell number in the hippocampus was observed in stressed rats, as a consequence of both decreased cell proliferation and increased apoptotic death. Decreases in BDNF and in the synaptic markers synaptophysin and PSD-95 were also found in MS rats. All these effects could be related to an HPA axis hyperactivity, as reflected in significant increases in corticosterone levels and decreases in glucocorticoid receptor expression. Further, SHSY5Y neuroblastoma cells treated with corticosterone showed increased BACE1, pTau and pJNK1 expression. In addition, venlafaxine, an antidepressant able to modulate HPA axis activity, reversed all the above cited deleterious effects of chronic stress, both in vivo and in vitro. It is proposed that the MS model can be considered as an appropriate experimental model for the study of sporadic AD.
authors.affiliation: Department of Pharmacology, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Martisova
authors.forename: Bárbara
authors.initials: B
authors.lastname: Aisa
authors.forename: Gorka
authors.initials: G
authors.lastname: Guereñu
authors.forename: María Javier
authors.initials: MJ
authors.lastname: Ramírez
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology / Q000523:psychology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides; D000818:Animals; D000831:Animals, Newborn; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D003511:Cyclohexanols / Q000008:administration & dosage; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008426:Maternal Deprivation; D008565:Membrane Proteins / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D010446:Peptide Fragments; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D016708:Synaptophysin / Q000378:metabolism; D000069470:Venlafaxine Hydrochloride; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018687:Antidepressive Agents, Second-Generation; D019208:Brain-Derived Neurotrophic Factor; D003511:Cyclohexanols; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D016708:Synaptophysin; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D000069470:Venlafaxine Hydrochloride; D048055:Mitogen-Activated Protein Kinase 8; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat