The Helico Maze Detects Early Impairment of Reference Memory at Three Months of Age in the 5XFAD Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Migliorati, Martine^{a; 1} | Manrique, Christine^{a; 1} | Rahrah, Melinda^a | Escoffier, Guy^a | El Ahmadi, Abdessadek^b | Girard, Stéphane D.^c | Khrestchatisky, Michel^a | Rivera, Santiago^a | Baranger, Kévin^{a; 2} | Roman, François S.^{a; *}

Affiliations: [a] Aix-Marseille University, CNRS, Institute of NeuroPhysiopathology, Marseille, France | [b] Aix-Marseille University, CNRS, Marseille, France | [c] VECT-HORUS SAS, Faculty of Medicine, Marseille, France

Correspondence: [*] Correspondence to: Pr. François S. Roman, INP Institut de Neurophysiopathologie, UMR 7051 CNRS - Aix-Marseille Université, Neurobiologie des Processus Mnésiques, Aix-Marseille Université, Faculté de Médecine/Campus Timone, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 05, France. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Note: [2] Present address: LIENSs UMRi CNRS 7266, BCBS group (Biotechnologies et Chimie des Bioressources pour la Santé), La Rochelle Université, France.

Abstract: Background:The 5XFAD model of Alzheimer’s disease (AD) bearing five familial mutations of Alzheimer’s disease on human APP and PSEN1 transgenes shows deposits of amyloid-β peptide (Aβ) as early as 2 months, while deficits in long-term memory can be detected at 4 months using the highly sensitive olfactory-dependent tests that we previously reported. Objective:Given that detecting early dysfunctions in AD prior to overt pathology is of major interest in the field, we sought to detect memory deficits at earlier stages of the disease in 3-month-old male 5XFAD mice. Methods:To this end, we used the Helico Maze, a behavioral task that was recently developed and patented. This device allows deeper analysis of learning and subcategories of hippocampal-dependent long-term memory using olfactory cues. Results:Eight male 5XFAD and 6 male wild-type (WT: C57Bl6 background) mice of 3 months of age were tested in the Helico Maze. The results demonstrated, for the first time, a starting deficit of pure reference long-term memory. Interestingly, memory impairment was clearly correlated with Aβ deposits in the hippocampus. While we also found significant differences in astrogliosis between 5XFAD and WT mice, this was not correlated with memory abilities. Conclusion:Our results underline the efficiency of this new olfactory-dependent behavioral task, which is easy to use, with a small cohort of mice. Using the Helico Maze may open new avenues to validate the efficacy of treatments that target early events related to the amyloid-dependent pathway of the disease and AD progression.

Keywords: Alzheimer’s disease, astrogliosis, 5XFAD mouse, Helico Maze, hippocampal Aβ deposits, reference memory deficit

DOI: 10.3233/JAD-220281

Journal: Journal of Alzheimer's Disease, vol. 90, no. 1, pp. 251-262, 2022