title: Reduced plasticity and mild cognitive impairment-like deficits after entorhinal lesions in hAPP/APOE4 mice.
abstract: Mild cognitive impairment (MCI) is a clinical condition that often precedes Alzheimer disease (AD). Compared with apolipoprotein E-ε3 (APOE3), the apolipoprotein E-ε4 (APOE4) allele is associated with an increased risk of developing MCI and spatial navigation impairments. In MCI, the entorhinal cortex (EC), which is the main innervation source of the dentate gyrus, displays partial neuronal loss. We show that bilateral partial EC lesions lead to marked spatial memory deficits and reduced synaptic density in the dentate gyrus of APOE4 mice compared with APOE3 mice. Genotype and lesion status did not affect the performance in non-navigational tasks. Thus, partial EC lesions in APOE4 mice were sufficient to induce severe spatial memory impairments and synaptic loss in the dentate gyrus. In addition, lesioned APOE4 mice showed no evidence of reactional increase in cholinergic terminals density as opposed to APOE3 mice, suggesting that APOE4 interferes with the ability of the cholinergic system to respond to EC input loss. These findings provide a possible mechanism underlying the aggravating effect of APOE4 on the cognitive outcome of MCI patients.
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives, UMR 7364 CNRS, Université de Strasbourg, Strasbourg, France.
authors.forename: Jean-Bastien
authors.initials: JB
authors.lastname: Bott
authors.forename: Brigitte
authors.initials: B
authors.lastname: Cosquer
authors.forename: Céline
authors.initials: C
authors.lastname: Héraud
authors.forename: Celina
authors.initials: C
authors.lastname: Zerbinatti
authors.forename: Christian
authors.initials: C
authors.lastname: Kelche
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Cassel
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathis
mesh_terms: D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics; D001284:Atrophy / Q000209:etiology / Q000235:genetics; D001930:Brain Injuries / Q000150:complications* / Q000235:genetics / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics; D003623:Dark Adaptation / Q000235:genetics; D018728:Entorhinal Cortex / Q000473:pathology*; D018846:Excitatory Amino Acids / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000633:toxicity; D021641:Recognition, Psychology / Q000502:physiology; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; D018846:Excitatory Amino Acids; D016202:N-Methylaspartate
keywords: Acetylcholine; Alzheimer disease (AD); Apolipoprotein E; Dentate gyrus; Entorhinal cortex; Mild cognitive impairment; Reactive synaptogenesis; Spatial navigation memory