Figure 2.

Interactions of Ca²⁺ and the neuronal cytoskeleton in AD pathogenesis. A. In healthy neurons the axon contains relatively high amounts of microtubules which are stabilized by the protein tau. Microtubule dynamics in axons play pivotal roles in organellar (mitochondria, for example) and protein transport to presynaptic axon terminals. Dendrites receive synaptic inputs in postsynaptic structures called spines whose shape is controlled by actin filaments and various scaffolding proteins. Ca²⁺ influx during synaptic activity modifies the dynamics of actin and microtubules in ways that allow the neuron to adapt to environmental demands. B. During the course of AD tau becomes hyperphosphorylated and dissociates from microtubules which then depolymerize. The hyperphosphorylated tau self-aggregates and accumulates in the cell body where it forms paired-helical filaments (neurofibrillary tangles). As a consequence of accumulation of Aβ at synapses, Ca²⁺ regulation is impaired, the dendritic spines atrophy and the underlying cytoskeletal scaffold is disrupted resulting in synaptic degeneration. In these ways, cytoskeletal abnormalities underlie cognitive impairment in AD.