How do neurons age? A focused review on the aging of the microtubular cytoskeleton

Abstract

Aging is the leading risk factor for Alzheimer's disease and other neurodegenerative diseases. We now understand that a breakdown in the neuronal cytoskeleton, mainly underpinned by protein modifications leading to the destabilization of microtubules, is central to the pathogenesis of Alzheimer's disease. This is accompanied by morphological defects across the somatodendritic compartment, axon, and synapse. However, knowledge of what occurs to the microtubule cytoskeleton and morphology of the neuron during physiological aging is comparatively poor. Several recent studies have suggested that there is an age-related increase in the phosphorylation of the key microtubule stabilizing protein tau, a modification, which is known to destabilize the cytoskeleton in Alzheimer's disease. This indicates that the cytoskeleton and potentially other neuronal structures reliant on the cytoskeleton become functionally compromised during normal physiological aging. The current literature shows age-related reductions in synaptic spine density and shifts in synaptic spine conformation which might explain age-related synaptic functional deficits. However, knowledge of what occurs to the microtubular and actin cytoskeleton, with increasing age is extremely limited. When considering the somatodendritic compartment, a regression in dendrites and loss of dendritic length and volume is reported whilst a reduction in soma volume/size is often seen. However, research into cytoskeletal change is limited to a handful of studies demonstrating reductions in and mislocalizations of microtubule-associated proteins with just one study directly exploring the integrity of the microtubules. In the axon, an increase in axonal diameter and age-related appearance of swellings is reported but like the dendrites, just one study investigates the microtubules directly with others reporting loss or mislocalization of microtubule-associated proteins. Though these are the general trends reported, there are clear disparities between model organisms and brain regions that are worthy of further investigation. Additionally, longitudinal studies of neuronal/cytoskeletal aging should also investigate whether these age-related changes contribute not just to vulnerability to disease but also to the decline in nervous system function and behavioral output that all organisms experience. This will highlight the utility, if any, of cytoskeletal fortification for the promotion of healthy neuronal aging and potential protection against age-related neurodegenerative disease. This review seeks to summarize what is currently known about the physiological aging of the neuron and microtubular cytoskeleton in the hope of uncovering mechanisms underpinning age-related risk to disease.

Figure 1

Graphical summary of age-related changes that occur to the morphology of synaptic spines. Research shows a general decrease in density of synaptic spines with age which is often characterized by the selective loss of thin spine types. Though it has not been studied extensively, the aging cytoskeleton within the synapse sees decreases in actin itself alongside actin binding proteins Drebrin and Cofilin. This is accompanied by an increase in the non-functional phosphorylated cofilin. Functionally, there is an increase in L-type calcium channels with age. White circles show cofilin proteins whilst brown circles represent Drebrin. Yellow (P) symbols represent phosphorylation. Created with BioRender.com.

Figure 2

Graphical representation of age-related changes occurring to the morphology of the somatodendritic and axonal neuronal compartments and the cytoskeleton. Evidence shows an age-related loss of and regression to dendrites (a) alongside a thinning and reduction in dendritic volume (b). Within the dendrites there is a loss of tubulin, tau, and MAP2 whilst tubulin is reduced in the soma and tau + P-Tau is mislocalized to the soma (c). In the axon, there can be increases in axonal diameter and the appearance of swellings (d). Normal tau is reduced and phosphorylated tau is increased whilst both also appear to mislocalize to the cell soma (e). EM studies show a disruption in the organization and morphology of microtubules (f) whilst axonal transport is interrupted (g) and GTPase derived tubulin turnover altered (h). Green circles represent MAP2 proteins, Red symbols represent tau proteins, purple circles represent tubulin, and blue (P) symbols represent phosphorylation. Created with BioRender.com. EM: Electron-microscopy; MAP: microtubule-associated protein; MTs: microtubules; p-Tau: phosphorylated tau.