Cell-autonomous reduction of CYFIP2 is insufficient to induce Alzheimer’s disease-like pathologies in the hippocampal CA1 pyramidal neurons of aged mice

다국어 초록 (Multilingual Abstract)

Cytoplasmic FMR1-interacting protein 2 (CYFIP2) is an evolutionarily conserved multifunctionalprotein that regulates the neuronal actin cytoskeleton, mRNA translation and transport, andmitochondrial morphology and function. Supporting its critical roles in proper neuronaldevelopment and function, human genetic studies have repeatedly identified variants of theCYFIP2 gene in individuals diagnosed with neurodevelopmental disorders. Notably, a fewrecent studies have also suggested a mechanistic link between reduced CYFIP2 level andAlzheimer’s disease (AD). Specifically, in the hippocampus of 12-month-old Cyfip2heterozygous mice, several AD-like pathologies were identified, including increased levels ofTau phosphorylation and gliosis, and loss of dendritic spines in CA1 pyramidal neurons.
However, detailed pathogenic mechanisms, such as cell types and their circuits where thepathologies originate, remain unknown for AD-like pathologies caused by CYFIP2 reduction.
In this study, we aimed to address this issue by examining whether the cell-autonomousreduction of CYFIP2 in CA1 excitatory pyramidal neurons is sufficient to induce AD-likephenotypes in the hippocampus. We performed immunohistochemical, morphological, andbiochemical analyses in 12-month-old Cyfip2 conditional knock-out mice, which havepostnatally reduced CYFIP2 expression level in CA1, but not in CA3, excitatory pyramidalneurons of the hippocampus. Unexpectedly, we could not find any significant AD-likephenotype, suggesting that the CA1 excitatory neuron-specific reduction of CYFIP2 level isinsufficient to lead to AD-like pathologies in the hippocampus. Therefore, we propose thatCYFIP2 reduction in other neurons and/or their synaptic connections with CA1 pyramidalneurons may be critically involved in the hippocampal AD-like phenotypes of Cyfip2heterozygous mice.