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Cited by 55Neuroscience and Neuropharmacology ResearchAlzheimer's disease research and treatmentsGenetics and Neurodevelopmental Disorders

Cyclase-associated protein 2 dimerization regulates cofilin in synaptic plasticity and Alzheimer's disease

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Pelucchi, Silvia, Vandermeulen, Lina, Pizzamiglio, Lara, Aksan, Bahar, Yan, Jing, Konietzny, Anja, Bonomi, Elisa, Borroni, Barbara +10 more·2020·Brain Communications
DOI 10.1093/braincomms/fcaa086PMC PMC7566557

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Abstract

Regulation of actin cytoskeleton dynamics in dendritic spines is crucial for learning and memory formation. Hence, defects in the actin cytoskeleton pathways are a biological trait of several brain diseases, including Alzheimer's disease. Here, we describe a novel synaptic mechanism governed by the cyclase-associated protein 2, which is required for structural plasticity phenomena and completely disrupted in Alzheimer's disease. We report that the formation of cyclase-associated protein 2 dimers through its Cys32 is important for cyclase-associated protein 2 binding to cofilin and for actin turnover. The Cys32-dependent cyclase-associated protein 2 homodimerization and association to cofilin are triggered by long-term potentiation and are required for long-term potentiation-induced cofilin translocation into spines, spine remodelling and the potentiation of synaptic transmission. This mechanism is specifically affected in the hippocampus, but not in the superior frontal gyrus, of both Alzheimer's disease patients and APP/PS1 mice, where cyclase-associated protein 2 is down-regulated and cyclase-associated protein 2 dimer synaptic levels are reduced. Notably, cyclase-associated protein 2 levels in the cerebrospinal fluid are significantly increased in Alzheimer's disease patients but not in subjects affected by frontotemporal dementia. In Alzheimer's disease hippocampi, cofilin association to cyclase-associated protein 2 dimer/monomer is altered and cofilin is aberrantly localized in spines. Taken together, these results provide novel insights into structural plasticity mechanisms that are defective in Alzheimer's disease.

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  • There is no clear evidence of CFL1 and CAP1 changes in AD.

    “Although there is no clear evidence of CFL1 and CAP1 changes in AD [28, 72],”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [72]

    The Results section, “Synaptic localization of CAP2 and cofilin is impaired in Alzheimer’s disease hippocampi” (page unavailable), reports no change in CAP1 total levels in the hippocampus or superior frontal gyrus of AD patients. It also reports a significant increase in hippocampal synaptic cofilin levels, so the broad claim that there is no clear evidence of cofilin/CFL1 changes is not supported, although total cofilin levels were unchanged. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Pelucchi, S., Vandermeulen, L., Pizzamiglio, L., Aksan, B., Yan, J., Konietzny, A., Bonomi, E., Borroni, B., Padovani, A., Rust, M. B., Di Marino, D., Mikhaylova, M., Mauceri, D., Antonucci, F., Edefonti, V., Gardoni, F., Di Luca, M., & Marcello, E.
Affiliations
  • University of Milan (IT)
  • Heidelberg University (DE)
  • University Medical Center Hamburg-Eppendorf (DE)
  • University of Brescia (IT)
  • Philipps University of Marburg (DE)
  • Department of Life and Environmental Sciences, New York-Marche Structural Biology Center (NY-MaSBiC), Polytechnic University of Marche, Via Brecce Bianche, Ancona, Italy
  • Humboldt-Universität zu Berlin (DE)
  • Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
ORCID
Venue
Brain Communications
Publisher
Oxford University Press (OUP)
Published
2020
Volume
2
Issue
2
Pages
fcaa086-fcaa086
ISSN
2632-1297 (ISSN-L)
DOI
10.1093/braincomms/fcaa086
PMC
PMC7566557
OpenAlex
W3037308374
Cited by
55
References
10
Citations by year
2026: 7 · 2025: 12 · 2024: 5 · 2023: 7 · 2022: 12 · 2021: 9 · 2020: 3
FWCI
3.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Communications (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
  • Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, cc-by)
Funders
  • European Union’s Horizon 2020 research and innovation program
  • Marie Skłodowska-Curie (676144)
  • Italian Ministry of Education
  • University and Research (2015N4FKJ4, 2017B9NCSX)
  • Fondazione Cariplo (2018—0511)
  • intramural grant of University of Milan (2—PSR2015-1716GRACA02_05_M, PSR2017_DIP_022_03, PSR2019_EMARC, PSR2015-1719FBRAV)
  • Deutsche Forschungsgemeinschaft (FOR2419)
  • MIUR - PON ‘Ricerca e Innovazione’ PerMedNet project (ARS01_01226)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
cofilin, protein dimerization, actin cytoskeleton dynamics, dendritic spines, synaptic plasticity, long-term potentiation, Alzheimer's disease, hippocampus, APP/PS1 mice, cerebrospinal fluid biomarkers, synaptic transmission, structural plasticity, frontotemporal dementia

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