The title of my talk: The cyclase-associated protein 2 is a novel regulator of cofilin in synaptic plasticity and Alzheimer’s disease.
Abstract: Morphological changes in dendritic spines are crucial for learning and memory formation. Hence, defects in spines are a common trait of several neurological disorders such as Alzheimer’s Disease (AD). Despite the relevance in AD pathogenesis, our knowledge about the mechanisms underlying synaptic failure in AD remains still fragmented. Although β-amyloid (Aβ) oligomers are considered the main drivers of synaptic dysfunction in AD, how they affect actin cytoskeleton, which confers structural and functional integrity to spines, remains controversial. Cofilin is one of the major regulators of actin dynamics in spines and is considered to be a trigger of the synaptotoxicity of the early phases of AD pathophysiology. Here, we describe the cyclase-associated protein 2 (CAP2) as a novel master regulator of cofilin localization in dendritic spines. CAP2 is a protein critical for neuronal architecture, spine morphology and synaptic function. The formation of CAP2 dimers through its Cys32 is important for CAP2 binding to cofilin and for normal spine actin turnover. We show that long-term potentiation (LTP) induction promotes the formation of Cys32-dependent CAP2 dimers and association with cofilin. The CAP2 dimerization through Cys32 is necessary for LTP-induced cofilin translocation into spines, for spine remodeling and for the potentiation of synaptic transmission. Remarkably, in AD patients’ hippocampi CAP2 is down-regulated, CAP2 dimer levels are reduced and cofilin is aberrantly localized in spines. In addition, this mechanism is an initial target of Aβ oligomers, which disrupt CAP2 association with cofilin and decrease the synaptic localization of both proteins. Taken together, these results provide novel insights into structural plasticity mechanisms that are defective in AD.
Bio: Elena Marcello is associate professor at University of Milan. She studied Pharmaceutical Biotechnology and in 2006 she received her Ph.D. in Pharmacology, Pharmacotoxicology and Pharmaceutical Biotechnology from University of Milan, Italy. Since then she has been interested in studying the pathogenesis of Alzheimer disease (AD) and the main aim of her research activity is to identify and characterize new pharmacological targets for AD therapy. During her PhD, she drew her attention to find out a molecular linker between primary and secondary pathogenic events in AD, namely the amyloid cascade and synaptic dysfunction associated to the glutamatergic system. She studied the trafficking mechanisms regulating the activity of ADAM10, a synaptic enzyme that prevents amyloid formation and works as sheddase towards several neuronal cell adhesion molecules. During her postdoc in Isabel Perez-Otano lab, Pamplona, Spain, she focused on the ER retention signal that regulates ADAM10 ER exit. Afterwards, in Prof. Di Luca lab at University of Milan, she dissected the endocytosis process of the enzyme at the synapse. She demonstrated that both ADAM10 forward trafficking and its endocytosis are regulated by activity-dependent synaptic plasticity and are required for a proper structural plasticity of the spines. Importantly, these pathways and the association of ADAM10 with its protein partners are severely affected in AD patients. Her current focus is on developing new molecules to target such pathological alterations associated with AD and on identifying novel pathways responsible for synaptic failure in AD.