Cell-autonomous reduction of CYFIP2 is insufficient to induce Alzheimer's disease-like pathologies in the hippocampal CA1 pyramidal neurons of aged mice
Open accessAbstract
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.
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Several AD-like pathologies, including Aβ accumulation, tau hyperphosphorylation, gliosis, and dendritic spine loss in the hippocampus, have been observed in heterozygous Cyfip2 knockout mice but not in mice with a neuron-specific conditional knockout of Cyfip2.
“Several AD-like pathologies, including Aβ accumulation, tau hyperphosphorylation, gliosis and dendritic spine loss in the hippocampus, have been observed in heterozygous Cyfip2 KO mice153,155 but not in mice with a neuron-specific conditional KO of Cyfip2156.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [156]
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“…of CYFIP1 and CYFIP2 can contribute to the morphological and functional changes in neuronal synapses observed in both Cy fi p1 and Cy fi p2 mutant mice (Bozdagi et al. 2012; Pathania et al. 2014; Han et al. 2015; Davenport et al. 2019; Lee SH et al. 2020; Zhang et al. 2020; Kim NS et al. 2022).”
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The WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
Self-citation
- Authors
- Ma, R., Zhang, Y., Li, H., Kang, H. R., Kim, Y., & Han, K.
- Affiliations
- Korea University (KR)
- Corresponding author
- Han, Kihoon
- Venue
- Animal Cells and Systems
- Publisher
- Informa UK Limited
- Published
- 2023-03-24
- Volume
- 27
- Issue
- 1
- Pages
- 94-102
- ISSN
- 1976-8354 (ISSN-L)
- 2151-2485
- PMC
- PMC10044167
- OpenAlex
- W4360841911
- Cited by
- 7
- References
- 6
- Citations by year
- 2025: 2 · 2024: 5
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Animal Cells and Systems (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Research Foundation of Korea
- Korea Government Ministry of Science (NRF-2018M3C7A1024603)
- Korea University (K2206011)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CYFIP2, Alzheimer's disease, CA1 pyramidal neurons, conditional knockout mice, tau phosphorylation, gliosis, dendritic spines, actin cytoskeleton, mRNA translation, mitochondrial function, neurodevelopmental disorders
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