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

Aging Brain

Chantal Mathis¹  Shoko Hashimoto²  Takaomi C. Saido²  Takashi Saito²  Christopher Borcuk³  Jil Scuto³  Céline Héraud³  Romain Goutagny³  Margot Diringer³  Demian Battaglia³  Élodie Panzer³  Karine Herbeaux³ 

[1] University of Strasbourg Institute for Advanced Studies (USIAS), F-67000 Strasbourg, France;Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan;Université de Strasbourg, CNRS, Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA) UMR 7364, F-67000 Strasbourg, France;

关键词: Preclinical Alzheimer disease;    Functional connectivity;    Associative memory;    Medial temporal cortex;    Claustrum;    Retrosplenial cortex;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown