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

International audienceAlzheimer'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 b (Ab) peptide induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of Ab-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 Ab levels are still low. We showed that TgCRND8 mice present alterations in hippocampal inhibitory networks and g 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 Ab-independent. Our results could partly explain the limited efficacy of Ab-directed treatments and favor multitherapy approaches for early symptomatic treatment for AD

Precocious Alterations of Brain Oscillatory Activity in Alzheimer’s Disease: A Window of Opportunity for Early Diagnosis and Treatment

International audienceAlzheimer's disease (AD) is the most common form of neurodegenerative dementia accounting for 50-80% of all age-related dementia. This pathology is characterized by the progressive and irreversible alteration of cognitive functions, such as memory, leading inexorably to the loss of autonomy for patients with AD. The pathology is linked with aging and occurs most commonly around 65 years old. Its prevalence (5% over 65 years of age and 20% after 80 years) constitutes an economic and social burden for AD patients and their family. At the present, there is still no cure for AD, actual treatments being moderately effective only in early stages of the pathology. A lot of efforts have been deployed with the aim of defining new AD biomarkers. Successful early detection of mild cognitive impairment (MCI) linked to AD requires the identification of biomarkers capable of distinguishing individuals with early stages of AD from other pathologies impacting cognition such as depression. In this article, we will review recent evidence suggesting that electroencephalographic (EEG) recordings, coupled with behavioral assessments, could be a useful approach and easily implementable for a precocious detection of AD