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International audience; 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.

Different memory systems operate in parallel to support behaviour. To evaluate procedural and reference subcategories of long-term memory as early as possible in the mouse, the Helico Maze (HM) was developed. BALB/c AnNCrl (BALB), C57BL/6JRj (C57) and DBA/2 JRj (DBA) mice were trained on this new maze. The three strains learned how to use the HM (procedural memory), and they then learned and remembered four odour-reward associations (reference memory). The three strains differed in the number of correct responses. BALB mice showed better performance than C57 and DBA mice. The results of the first block of each session revealed that only the BALB and C57 mice remembered the odour-reward associations. DBA mice needed to relearn the associations each day. With this new apparatus, the number of olfactory cue-reward associations was increased from 2 to 4 in comparison to a previous olfactory tubing maze. Consequently, a supplementary effort of memory was required, and the chance level was decreased from 50 % to 25 %. Thus, in several important respects, the HM can be considered to measure the hippocampus-dependent behaviour of the mouse, allowing to study, as early as possible in young mice, the different subcategories of long-term memory, such as those observed in humans.