title: Decrease of ERK/MAPK overactivation in prefrontal cortex reverses early memory deficit in a mouse model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) can be considered as a disease of memory in its initial clinical stages. Amyloid-β (Aβ) peptide accumulation is central to the disease initiation leading later to intracellular neurofibrillary tangles (NFTs) of cytoskeletal tau protein formation. It is under discussion whether different Aβ levels of aggregation, concentration, brain area, and/or time of exposure might be critical to the disease progression, as well as which intracellular pathways it activates. The aim of the present work was to study memory-related early molecular and behavioral alterations in a mouse model of AD, in which a subtle deregulation of the physiologic function of Aβ can be inferred. For this purpose we used triple-transgenic (3xTg) mice, which develop Aβ and tau pathology resembling the disease progression in humans. Memory impairment in novel object recognition task was evident by 5 months of age in 3xTg mice. Hippocampus and prefrontal cortex extra-nuclear protein extracts developed differential patterns of Aβ aggregation. ERK1/MAPK showed higher levels of cytosolic activity at 3 months and higher levels of nuclear activity at 6 months in the prefrontal cortex. No significant differences were found in JNK and NF-κB activity and in calcineurin protein levels. Finally, intra-PFC administration of a MEK inhibitor in 6-month-old 3xTg mice was able to reverse memory impairment, suggesting that ERK pathway alterations might at least partially explain memory deficits observed in this model, likely as a consequence of memory trace disruption.
authors: Laboratorio de Neurobiología de la Memoria, Dto. Fisiología, Biología Molecular y Celular, Fac. Cs. Exactas y Naturales, UBA/IFIByNE, CONICET, CABA, Argentina.
authors: Mariana
authors: M
authors: Feld
authors: Laboratorio de Neurofarmacología de los Procesos de Memoria, Cátedra de Farmacología, Fac. Farmacia y Bioquímica, UBA, CABA, Argentina.
authors: María C
authors: MC
authors: Krawczyk
authors: Laboratorio de Neurobiología de la Memoria, Dto. Fisiología, Biología Molecular y Celular, Fac. Cs. Exactas y Naturales, UBA/IFIByNE, CONICET, CABA, Argentina.
authors: M
authors: M
authors: Sol Fustiñana
authors: Laboratorio de Neurofarmacología de los Procesos de Memoria, Cátedra de Farmacología, Fac. Farmacia y Bioquímica, UBA, CABA, Argentina.
authors: Mariano G
authors: MG
authors: Blake
authors: Laboratorio de Neurofarmacología de los Procesos de Memoria, Cátedra de Farmacología, Fac. Farmacia y Bioquímica, UBA, CABA, Argentina.
authors: Carlos M
authors: CM
authors: Baratti
authors: Laboratorio de Neurobiología de la Memoria, Dto. Fisiología, Biología Molecular y Celular, Fac. Cs. Exactas y Naturales, UBA/IFIByNE, CONICET, CABA, Argentina.
authors: Arturo
authors: A
authors: Romano
authors: Laboratorio de Neurofarmacología de los Procesos de Memoria, Cátedra de Farmacología, Fac. Farmacia y Bioquímica, UBA, CABA, Argentina.
authors: Mariano M
authors: MM
authors: Boccia
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008569:Memory Disorders / Q000201:enzymology / Q000209:etiology* / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D017397:Prefrontal Cortex / Q000378:metabolism*; D021641:Recognition, Psychology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016875:tau Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: 3xTg mice; Alzheimer's disease; ERK; JNK; NF-κB; amyloid-β aggregation; calcineurin; object recognition memory