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

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 (CAP2), which is required for structural plasticity phenomena and completely disrupted in Alzheimer's Disease. We report that the formation of CAP2 dimers through its Cys32 is important for CAP2 binding to cofilin and for actin turnover. The Cys32-dependent CAP2 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 CAP2 is down-regulated and CAP2 dimer synaptic levels are reduced. Notably, CAP2 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 CAP2 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.

Direct interaction of HIV gp120 with neuronal CXCR4 and CCR5 receptors induces cofilin-actin rod pathology via a cellular prion protein- and NOX-dependent mechanism

“…Moreover, ROS produced by NOX can simultaneously activate slingshot-1, a phospho-cofilin phosphatase, by oxidizing and removing an inhibitory 14-3-3 family protein that helps maintain slingshot-1 in an inactive state [ 67 ]. Cofilin’s collaboration with Aip1/WDR1 supports actin filament severing and recruitment of oligomers of CAP1/2 to cofilin-actin fragments assists in their complete depolymerization [ 79 , 80 ].…”

CAPt’n of Actin Dynamics: Recent Advances in the Molecular, Developmental and Physiological Functions of Cyclase-Associated Protein (CAP)

“…In this framework, ABP are critical for the precise control of the actin cytoskeleton, since they are responsible for forming the F-actin structures at the right place and time within the cell. In light of these considerations, the actin cytoskeleton and, thereby, ABP play key roles in many aspects of human health, ranging from embryonic development to aging, and are implicated in several diseases and pathological processes including cancer metastasis, wound repair, inflammation or neurodegenerative disorders (Davidson and Wood, 2016;Lai and Wong, 2020;Pelucchi et al, 2020b). As far as concern CAP1 and CAP2, potential roles have been described for various human pathologies apart from the already mentioned contributions of CAP1 to atherosclerosis or other cardiovascular diseases and of CAP2 to heart diseases and 6p22 syndrome.…”

“…We have mentioned above the importance of CAP2 for synaptic plasticity that is relevant for learning and memory. F-actin alterations in dendritic spines have been described in AD, the most common form of dementia characterized by synaptic dysfunction in the early stages of the pathogenesis (Pelucchi et al, 2020b). CAP2 levels and synaptic localization are specifically reduced in the hippocampus, but not in the cortex of AD patients.…”

Functional Redundancy of Cyclase-Associated Proteins CAP1 and CAP2 in Differentiating Neurons

“…Differently from most other tissues, CAP1 and CAP2 are both expressed in the brain [ 10 , 11 ], and recent studies unraveled important functions for both in hippocampal neurons. Specifically, shRNA-mediated knockdown in isolated rat hippocampal neurons revealed a role for CAP2 in the morphology and function of dendritic spines [ 19 ], F-actin-enriched dendritic protrusions forming the postsynaptic compartment of most excitatory synapses in the brain [ 20 , 21 ]. Moreover, CAP2 dysregulation has been implicated in synaptic defects of Alzheimer’s disease [ 19 ].…”

“…Specifically, shRNA-mediated knockdown in isolated rat hippocampal neurons revealed a role for CAP2 in the morphology and function of dendritic spines [ 19 ], F-actin-enriched dendritic protrusions forming the postsynaptic compartment of most excitatory synapses in the brain [ 20 , 21 ]. Moreover, CAP2 dysregulation has been implicated in synaptic defects of Alzheimer’s disease [ 19 ]. Instead, hippocampal neurons from brain-specific CAP1-KO mice displayed an altered morphology and function of growth cones [ 9 ], dynamic F-actin-rich structures at the tip of neurites that sense environmental guidance cues and navigate axons through the developing brain to their target regions [ 22 ].…”