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.

Deficits in memory-guided limb movements impair obstacle avoidance locomotion in Alzheimer's disease mouse model

“…These findings were consistent with those of previous studies of AD patients, that is, they have impairments of memory-guided reaching movement but not visually-guided reaching movement2728. From an age of 10 months, 3xTg mice exhibit pathological changes in the extraparietal areas of the cerebral cortex such as the frontal and temporal lobes4142. Further studies are required to elucidate whether these pathological changes are related to alterations in working memory in 3xTg mice that might affect their ability to accurately execute memory-guided limb movements during locomotion.…”

A Rare Duplication on Chromosome 16p11.2 Is Identified in Patients with Psychosis in Alzheimer's Disease

“…MAZ was also identified as a blood biomarker in schizophrenia [39]. Accumulated evidence have shown that up-regulation of MAPK3 ( ERK1 ) are associated with the progression of Alzheimer's disease [40]–[44]. In addition, expression of MAPK3 is significantly associated with a locus (rs4583255[T]) on 16p11.2 which shows genome-wide significant association with psychosis, including schizophrenia, bipolar disorder and related psychoses by a recent GWAS (genome-wide association study) in a large cohort [45].…”

Targeting neuroinflammation in Alzheimer’s disease

“…Upstream of cytokines production is the activation of the nuclear factor-kappa B (NF-κB) pathway,77 and the subsequent activation of mitogen-activated protein kinase (MAPK) pathways, whose proinflammatory gene expression is Aβ dependent 78. Extracellular signal-regulated protein kinases (ERKs), stress-activated protein kinases c-Jun NH2-terminal kinase (JNK), and p38 constitute the set of MAPKs whose action is exerted both in the cytoplasm and in the nucleus, thereby phosphorylating transcription factors.…”