Cyclase-associated protein 2 dimerization regulates cofilin in synaptic plasticity and Alzheimer's disease
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Cyclase-associated protein 2 dimerization regulates cofilin in synaptic plasticity and Alzheimer's disease. / Pelucchi, Silvia; Vandermeulen, Lina; Pizzamiglio, Lara; Aksan, Bahar; Yan, Jing; Konietzny, Anja; Bonomi, Elisa; Borroni, Barbara; Padovani, Alessandro; Rust, Marco B; Di Marino, Daniele; Mikhaylova, Marina; Mauceri, Daniela; Antonucci, Flavia; Edefonti, Valeria; Gardoni, Fabrizio; Di Luca, Monica; Marcello, Elena.
in: BRAIN COMMUN, Jahrgang 2, Nr. 2, 26.06.2020, S. fcaa086.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Cyclase-associated protein 2 dimerization regulates cofilin in synaptic plasticity and Alzheimer's disease
AU - Pelucchi, Silvia
AU - Vandermeulen, Lina
AU - Pizzamiglio, Lara
AU - Aksan, Bahar
AU - Yan, Jing
AU - Konietzny, Anja
AU - Bonomi, Elisa
AU - Borroni, Barbara
AU - Padovani, Alessandro
AU - Rust, Marco B
AU - Di Marino, Daniele
AU - Mikhaylova, Marina
AU - Mauceri, Daniela
AU - Antonucci, Flavia
AU - Edefonti, Valeria
AU - Gardoni, Fabrizio
AU - Di Luca, Monica
AU - Marcello, Elena
N1 - © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2020/6/26
Y1 - 2020/6/26
N2 - 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.
AB - 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.
U2 - 10.1093/braincomms/fcaa086
DO - 10.1093/braincomms/fcaa086
M3 - SCORING: Journal article
C2 - 33094279
VL - 2
SP - fcaa086
JO - BRAIN COMMUN
JF - BRAIN COMMUN
SN - 2632-1297
IS - 2
ER -