| Title: |
Cyclase-associated protein 2 gene delivery: A potential multi-target approach for preventing synaptic failure in Alzheimer’s disease |
| Authors: |
Stringhi, Ramona; Pelucchi, Silvia; D'Andrea, Laura; La Greca, Filippo; Zianni, Elisa; Targa, Lorenzo; Mosconi, Cedric; Vandermeulen, Lina; Ascagni, Miriam; Speciani, Michela Carola; Gardoni, Fabrizio; Scheggia, Diego; Edefonti, Valeria; Di Luca, Monica; Marcello, Elena |
| Contributors: |
R. Stringhi; S. Pelucchi; L. D'Andrea; F. La Greca; E. Zianni; L. Targa; C. Mosconi; L. Vandermeulen; M. Ascagni; M.C. Speciani; F. Gardoni; D. Scheggia; V. Edefonti; M. Di Luca; E. Marcello |
| Publisher Information: |
Cell Press; Elsevier |
| Publication Year: |
2026 |
| Collection: |
The University of Milan: Archivio Istituzionale della Ricerca (AIR) |
| Subject Terms: |
Alzheimer disease; CAP2; actin; actin rod; amyloid; cofilin; glutamatergic synapse; hippocampu; synaptic resilience; tau; Settore BIOS-11/A - Farmacologia |
| Description: |
Alzheimer’s disease (AD) is marked by synaptic failure, with actin cytoskeleton alterations playing a key role in its pathogenesis. Cofilin, a regulator of actin dynamics in dendritic spines, forms cofilin-actin rods upon exposure to amyloid-β (Aβ) oligomers, contributing to synaptic loss. Cyclase-associated protein 2 (CAP2) is crucial for regulating cofilin activity. During long-term potentiation, CAP2 dimerization is relevant for cofilin translocation to spines required for spine remodeling. In AD, CAP2 is downregulated, thus disrupting synaptic CAP2/cofilin complexes. To investigate the neuroprotective potential of CAP2 overexpression in preventing Aβ-induced synaptic dysfunction, we used adeno-associated virus serotype 9 (AAV) gene delivery to elevate CAP2 levels in APP/PS1 mice—a model of amyloid pathology—starting from the asymptomatic stage. APP/PS1 animals received bilateral stereotaxic injection of either AAV expressing CAP2 or a control AAV. This approach preserved synaptic CAP2/cofilin interaction, maintained synaptic plasticity pathways, and sustained cognitive function. CAP2 overexpression reduced cofilin-actin rod formation and mitigated tau abnormalities. Notably, CAP2 is present in cofilin-actin rods, and its dimerization is required to prevent Aβ-driven synaptic loss but not to protect neurons from rod formation. These findings highlight CAP2 upregulation as a promising strategy to enhance neuronal resilience and counteract Aβ synaptic toxicity in AD. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/41388626; firstpage:1; lastpage:23; numberofpages:23; journal:MOLECULAR THERAPY; https://hdl.handle.net/2434/1221937 |
| DOI: |
10.1016/j.ymthe.2025.12.023 |
| Availability: |
https://hdl.handle.net/2434/1221937; https://doi.org/10.1016/j.ymthe.2025.12.023 |
| Rights: |
info:eu-repo/semantics/openAccess ; license:Creative commons ; license uri:http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.3E2633C6 |
| Database: |
BASE |