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.

Keywords: actin cytoskeleton; actin-binding proteins; amyloid; synaptic plasticity; synaptopathy.

Figure 1

Schematic representation of β-amyloid precursor protein (APP) processing. The vast majority of BACE1 cleavage of APP occurs into BACE1-containing acidic organelles via clathrin-dependent endocytosis. The subsequent γ-secretase activity determines the release of Aβ. Alternatively, APP can undergo a non-amyloidogenic pathway that involves the α-secretase ADAM10 and occurs largely on the plasma membrane and in the trans-Golgi network. Red arrow, exocytosis/endocytosis pathways; black arrows, enzymatic cleavage of APP.

Figure 2

Dendritic spine actin cytoskeleton dynamics in activity-dependent synaptic plasticity phenomena. During the first phase of long-term potentiation (LTP) (1–7 min), there is a rearrangement of the actin cytoskeleton characterized by (i) the increase in the synaptic level of actin-binding proteins that are able to modify F-actin through several process, such as severing (cofilin), branching (Arp2/3), or capping (Aip1); (ii) the decrease in actin-stabilizer proteins (drebrin, CaMKIIβ, and α-actinin) responsible for stabilizing actin filaments and linking them to the postsynaptic density (PSD). After this phase, cofilin is inactivated to enlarge the spine and stabilize changes in structure. During long-term depression (LTD), the spine shrinkage is associated to a decrease in spine actin filaments. The actin cytoskeleton and actin-binding proteins are also involved in AMPA receptor trafficking: LTP triggers AMPA receptor forward trafficking, while LTD promotes clathrin-mediated endocytosis of AMPA receptors.