Early memory deficits and extensive brain network disorganization in the AppNL-F/MAPT double knock-in mouse model of familial Alzheimer's disease

Christopher Borcuk; Céline Héraud; Karine Herbeaux; Margot Diringer; Élodie Panzer; Jil Scuto; Shoko Hashimoto; Takaomi C Saido; Takashi Saito; Romain Goutagny; Demian Battaglia; Chantal Mathis

doi:10.1016/j.nbas.2022.100042

Early memory deficits and extensive brain network disorganization in the App^NL-F/MAPT double knock-in mouse model of familial Alzheimer's disease

Aging Brain. 2022 Jun 2:2:100042. doi: 10.1016/j.nbas.2022.100042. eCollection 2022.

Authors

Affiliations

¹ Université de Strasbourg, CNRS, Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA) UMR 7364, F-67000 Strasbourg, France.
² Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan.
³ University of Strasbourg Institute for Advanced Studies (USIAS), F-67000 Strasbourg, France.
⁴ Université d'Aix-Marseille, Inserm, Institut de Neurosciences des Systèmes (INS) UMR_S 1106, F-13005 Marseille, France.

Abstract

A critical challenge in current research on Alzheimer's disease (AD) is to clarify the relationship between network dysfunction and the emergence of subtle memory deficits in itspreclinical stage. The AppNL-F/MAPT double knock-in (dKI) model with humanized β-amyloid peptide (Aβ) and tau was used to investigate both memory and network dysfunctions at an early stage. Young male dKI mice (2 to 6 months) were tested in three tasks taxing different aspects of recognition memory affected in preclinical AD. An early deficit first appeared in the object-place association task at the age of 4 months, when increased levels of β-CTF and Aβ were detected in both the hippocampus and the medial temporal cortex, and tau pathology was found only in the medial temporal cortex. Object-place task-dependent c-Fos activation was then analyzed in 22 subregions across the medial prefrontal cortex, claustrum, retrosplenial cortex, and medial temporal lobe. Increased c-Fos activation was detected in the entorhinal cortex and the claustrum of dKI mice. During recall, network efficiency was reduced across cingulate regions with a major disruption of information flow through the retrosplenial cortex. Our findings suggest that early perirhinal-entorhinal pathology is associated with abnormal activity which may spread to downstream regions such as the claustrum, the medial prefrontal cortex and ultimately the key retrosplenial hub which relays information from frontal to temporal lobes. The similarity between our findings and those reported in preclinical stages of AD suggests that the AppNL-F/MAPT dKI model has a high potential for providing key insights into preclinical AD.

Keywords: AD, Alzheimer’s disease; ADAD, autosomal dominant Alzheimer’s disease; Associative memory; CLA, claustrum; Claustrum; DMN, default mode network; EI, exploration index; FC, functional connectivity; Functional connectivity; MI, Memory index; MTC, medial temporal cortex; MTL, medial temporal lobe; Medial temporal cortex; NOR, novel object recognition; OL, Object location; OP, object-place; PS, Pattern Separation; Preclinical Alzheimer disease; Retrosplenial cortex; aMCI, amnestic mild cognitive impairment; amyloid beta, Aβ; dKI, AppNL-F/MAPT double knock-in; ptau Thr 181, Thr181phosphorylated tau protein.