title: An increase in Abeta42 in the prefrontal cortex is associated with a reversal-learning impairment in Alzheimer's disease model Tg2576 APPsw mice.
abstract: The medial temporal lobe-dependent memory loss associated with Alzheimer's disease (AD) is often accompanied by a loss of prefrontal cortex-dependent cognitive domains that fall under the broad category of executive function. In this study, we examined the relationship between one type of prefrontal-dependent executive function, discrimination reversal-learning, and levels of the amyloid beta protein (Abeta) of 40 and 42 residues in a transgenic mouse model (Tg2576) of the over-expression of the familial AD mutant form of the amyloid precursor protein (APPsw). Tg2576 and their non-transgenic (NTg) littermates were assessed at 3 and 6 months of age when there is little to no amyloid plaque deposition. After reversal-learning assessment, Abeta40 and Abeta42 were quantified in the prefrontal cortex and hippocampus. Tg2576 mice were impaired in reversal-learning at 6 but not 3 months of age when compared to the NTg group. Coincidently, there was a corresponding approximately 3-fold increase of Abeta42 levels in the prefrontal cortex of 6- compared to 3-month-old Tg2576 mice. In addition, the prefrontal cortex contained higher levels of Abeta42 compared to the hippocampus at both 3 and 6 months of age, regardless of genotype, indicating a high vulnerability of this brain region to Abeta42 accumulation. These data suggest that the early emergence of reversal-learning deficits in the Tg2576 mouse may be due to the localized increase of Abeta42 in the prefrontal cortex.
authors.affiliation: Mayo Clinic College of Medicine, Jacksonville, FL, USA.
authors.forename: Jia-Min
authors.initials: JM
authors.lastname: Zhuo
authors.forename: Annamalai
authors.initials: A
authors.lastname: Prakasam
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Zhang
authors.forename: Mark G
authors.initials: MG
authors.lastname: Baxter
authors.forename: Kumar
authors.initials: K
authors.lastname: Sambamurti
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Nicolle
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D004193:Discrimination Learning; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D007859:Learning Disabilities / Q000209:etiology* / Q000473:pathology*; D016014:Linear Models; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009812:Odorants; D010446:Peptide Fragments / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D012193:Reversal Learning / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)