Cyclase-associated protein 2 gene delivery: A potential multi-target approach for preventing synaptic failure in Alzheimer’s disease

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.