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Sci Adv. 2017 Feb 24;3(2):e1601068. doi: 10.1126/sciadv.1601068. eCollection 2017 Feb.

Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer's disease.

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Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), Université de Strasbourg, Faculté de Psychologie, 12 rue Goethe, F-67000 Strasbourg, France.; LNCA, UMR 7364, CNRS, Neuropôle de Strasbourg, 12 rue Goethe, F-67000 Strasbourg, France.


Alzheimer's disease (AD) is a neurodegenerative pathology commonly characterized by a progressive and irreversible deterioration of cognitive functions, especially memory. Although the etiology of AD remains unknown, a consensus has emerged on the amyloid hypothesis, which posits that increased production of soluble amyloid β (Aβ) peptide induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of Aβ-centric therapeutics suggest that the amyloid hypothesis is incomplete and/or that the treatments were given too late in the course of AD, when neuronal damages were already too extensive. Hence, it is striking to see that very few studies have extensively characterized, from anatomy to behavior, the alterations associated with pre-amyloid stages in mouse models of AD amyloid pathology. To fulfill this gap, we examined memory capacities as well as hippocampal network anatomy and dynamics in young adult pre-plaque TgCRND8 mice when hippocampal Aβ levels are still low. We showed that TgCRND8 mice present alterations in hippocampal inhibitory networks and γ oscillations at this stage. Further, these mice exhibited deficits only in a subset of hippocampal-dependent memory tasks, which are all affected at later stages. Last, using a pharmacological approach, we showed that some of these early memory deficits were Aβ-independent. Our results could partly explain the limited efficacy of Aβ-directed treatments and favor multitherapy approaches for early symptomatic treatment for AD.


CA1 area; Hippocampus; Parvalbumin; amyloid beta; beta-CTF; gamma rhythm; recognition memory

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