Impaired regulation of synaptic actin cytoskeleton in Alzheimer's disease

Abstract

Representing the most common cause of dementia, Alzheimer's disease (AD) has dramatically impacted the neurological and economic health of our society. AD is a debilitating neurodegenerative disease that produces marked cognitive decline. Much evidence has accumulated over the past decade to suggest soluble oligomers of beta-amyloid (Aβ) have a critical role in mediating AD pathology early in the disease process by perturbing synaptic efficacy. Here we critically review recent research that implicates synapses as key sites of early pathogenesis in AD. Most excitatory synapses in the brain rely on dendritic spines as the sites for excitatory neurotransmission. The structure and function of dendritic spines are dynamically regulated by cellular pathways acting on the actin cytoskeleton. Numerous studies analyzing human postmortem tissue, animal models and cellular paradigms indicate that AD pathology has a deleterious effect on the pathways governing actin cytoskeleton stability. Based on the available evidence, we propose the idea that a contributing factor to synaptic pathology in early AD is an Aβ oligomer-initiated collapse of a "synaptic safety net" in spines, leading to dendritic spine degeneration and synaptic dysfunction. Spine stabilizing pathways may thus represent efficacious therapeutic targets for combating AD pathology.

Figure 1

Depiction of dendrites and dendritic spines found on cortical neurons. (A) Representative cultured cortical neuron expressing green fluorescent protein (GFP). Dendrites extend from the soma and exhibit extensive branching, composing the neuron’s dendritic arbor. Dendritic spines protrude form dendrites allowing neurons to make synaptic connections. Notice that the axon is thinner than dendrites and does not have spines. (B) Magnified image of a dendrite expressing GFP. Dendritic spines have a bulbous head, which serves as the site of synaptic contact, and a thinner neck connected to the dendrite. (C) Model of a dendritic spine synapsing with an axon. The postsynaptic density (PSD) anchors synaptic proteins, including glutamate receptors (e.g. NMDARs and AMPARs), at the synapse. The dynamic actin cytoskeleton confers much of the structure and function of the dendritic spine.

Figure 2

AD-related pathology causes synaptic dysfunction. (A) Cultured cortical neuron over-expressing kalirin-7 (green), stained for drebrin (blue) and treated with fluorescent Aβ oligomers (also called ADDLs, red). White indicates co-localization, demonstrating ADDLs bind excitatory synapses. (B) Dendrite and spines of a cortical neuron (green) treated with fluorescent ADDLs (cyan). Aβ oligomers clearly bind dendritic spines, with co-localization shown in white (indicated by grey arrows). (C) Soluble Aβ oligomers downregulate many of the key molecular players responsible for maintaining the actin cytoskeleton, and also upregulate the activity of proteins that weaken the actin cytoskeleton (loss of the “synaptic safety net”). As a result, the mechanisms regulating synaptic plasticity become dysregulated whereby increased actin destabilization could precipitate collapse of the dendritic spine and ultimately loss of functional synapses.