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

Ruiying Ma, Yinhua Zhang, Huiling Li, Hyae Rim Kang, Yoonhee Kim, Kihoon Han

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Cytoplasmic FMR1-interacting protein 2 (CYFIP2) is an evolutionarily conserved multifunctional protein that regulates the neuronal actin cytoskeleton, mRNA translation and transport, and mitochondrial morphology and function. Supporting its critical roles in proper neuronal development and function, human genetic studies have repeatedly identified variants of the CYFIP2 gene in individuals diagnosed with neurodevelopmental disorders. Notably, a few recent studies have also suggested a mechanistic link between reduced CYFIP2 level and Alzheimer's disease (AD). Specifically, in the hippocampus of 12-month-old Cyfip2 heterozygous mice, several AD-like pathologies were identified, including increased levels of Tau phosphorylation and gliosis, and loss of dendritic spines in CA1 pyramidal neurons. However, detailed pathogenic mechanisms, such as cell types and their circuits where the pathologies 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-autonomous reduction of CYFIP2 in CA1 excitatory pyramidal neurons is sufficient to induce AD-like phenotypes in the hippocampus. We performed immunohistochemical, morphological, and biochemical analyses in 12-month-old Cyfip2 conditional knock-out mice, which have postnatally reduced CYFIP2 expression level in CA1, but not in CA3, excitatory pyramidal neurons of the hippocampus. Unexpectedly, we could not find any significant AD-like phenotype, suggesting that the CA1 excitatory neuron-specific reduction of CYFIP2 level is insufficient to lead to AD-like pathologies in the hippocampus. Therefore, we propose that CYFIP2 reduction in other neurons and/or their synaptic connections with CA1 pyramidal neurons may be critically involved in the hippocampal AD-like phenotypes of Cyfip2 heterozygous mice.

Original languageEnglish
Pages (from-to)93-101
Number of pages9
JournalAnimal Cells and Systems
Volume27
Issue number1
DOIs
Publication statusPublished - 2023

Bibliographical note

Funding Information:
This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korea Government Ministry of Science and ICT (NRF-2018M3C7A1024603 and NRF-2021R1A2C4001429 to KH, NRF-2022R1I1A1A01053508 to YZ) and by a Korea University grant (K2206011 to KH).

Publisher Copyright:
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Keywords

  • Alzheimer’s disease
  • CYFIP2
  • conditional knock-out
  • excitatory pyramidal neuron
  • hippocampal CA1

ASJC Scopus subject areas

  • Animal Science and Zoology
  • General Biochemistry,Genetics and Molecular Biology

Fingerprint

Dive into the research topics of 'Cell-autonomous reduction of CYFIP2 is insufficient to induce Alzheimer's disease-like pathologies in the hippocampal CA1 pyramidal neurons of aged mice'. Together they form a unique fingerprint.

Cite this