Dendritic Spines in Alzheimer’s Disease: How the Actin Cytoskeleton Contributes to Synaptic Failure

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ-driven synaptic dysfunction in the early phases of pathogenesis. In the synaptic context, the actin cytoskeleton is a crucial element to maintain the dendritic spine architecture and to orchestrate the spine’s morphology remodeling driven by synaptic activity. Indeed, spine shape and synaptic strength are strictly correlated and precisely governed during plasticity phenomena in order to convert short-term alterations of synaptic strength into long-lasting changes that are embedded in stable structural modification. These functional and structural modifications are considered the biological basis of learning and memory processes. In this review we discussed the existing evidence regarding the role of the spine actin cytoskeleton in AD synaptic failure. We revised the physiological function of the actin cytoskeleton in the spine shaping and the contribution of actin dynamics in the endocytosis mechanism. The internalization process is implicated in different aspects of AD since it controls both glutamate receptor membrane levels and amyloid generation. The detailed understanding of the mechanisms controlling the actin cytoskeleton in a unique biological context as the dendritic spine could pave the way to the development of innovative synapse-tailored therapeutic interventions and to the identification of novel biomarkers to monitor synaptic loss in AD.

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

“…A specific role of this domain in oligomerization will be discussed below. Notably, this domain also includes a conserved cysteine residue, which recently was implicated in covalent dimer formation, Cofilin1 interaction and regulation of actin dynamics (Liu et al, 2018;Pelucchi et al, 2020a).…”

“…Because CAP2 mutant mice displayed a delay in motor functions during postnatal development together with heart defects (Peche et al, 2012;Field et al, 2015;Kepser et al, 2019), a contribution of CAP2 loss to 6p22 syndrome has been suggested. Notably, apart from striated muscles, CAP2 is abundant in brain and present in different brain areas including cerebral cortex and hippocampus (Bertling et al, 2004;Peche et al, 2007;Kumar et al, 2016;Pelucchi et al, 2020a). In differentiated neurons, CAP2 is present in postsynaptic compartments (dendritic spines) of excitatory synapses and located in the F-actin enriched region underneath the postsynaptic density (Pelucchi et al, 2020a).…”

“…Notably, apart from striated muscles, CAP2 is abundant in brain and present in different brain areas including cerebral cortex and hippocampus (Bertling et al, 2004;Peche et al, 2007;Kumar et al, 2016;Pelucchi et al, 2020a). In differentiated neurons, CAP2 is present in postsynaptic compartments (dendritic spines) of excitatory synapses and located in the F-actin enriched region underneath the postsynaptic density (Pelucchi et al, 2020a). CAP2 inactivation differently affected neuron structure and dendritic spine morphology in cerebral cortex and hippocampus.…”

“…CAP2 inactivation differently affected neuron structure and dendritic spine morphology in cerebral cortex and hippocampus. While primary cortical neurons from CAP2 mutant mice showed an increase in dendrite complexity and spine density (Kumar et al, 2016), CAP2 downregulation in primary hippocampal neurons reduced dendritic arborization and enlarged spines, which was associated with decreased synaptic excitatory transmission and impaired synaptic plasticity (Pelucchi et al, 2020a). Interestingly, CAP2 function in spine morphology and synaptic plasticity required its ability to form disulfide cross-linked homodimers, which were mediated by cysteine-residues at position 32 (C32).…”

Ofloxacin as a Disruptor of Actin Aggresome “Hirano Bodies”: A Potential Repurposed Drug for the Treatment of Neurodegenerative Diseases

“…Actin is reported to be the driving force in controlling synaptic plasticity and maintaining the structural integrity of the synapses ( Kim and Lisman, 1999 ; Luo, 2002 ; Fukazawa et al, 2003 ; Bourne and Harris, 2008 ; Okada and Soderling, 2009 ). It functions by changing its morphology in response to different types of neural activity ( Svennberg, 2006 ; Gordon-Weeks and Fournier, 2014 ; Spence and Soderling, 2015 ; Szabó et al, 2016 ; Pelucchi et al, 2020 ). Defects in the regulation of actin protein is one of the contributing factors leading to neurological disorders ( Kim and Lisman, 1999 ; Luo, 2002 ; Bourne and Harris, 2008 ; Okada and Soderling, 2009 ).…”