Aging Does Not Affect Axon Initial Segment Structure and Somatic Localization of Tau Protein in Hippocampal Neurons ofFischer344 Rats

Abstract

Little is known about the specific contributions of aging to the neuron dysfunction and death in Alzheimer’s disease (AD). AD is characterized by the pathological accumulation of abnormal tau (a microtubule-associated protein), and the mislocalization of tau from the axon to the somatodendritic compartment is thought to play an important role in disease pathogenesis. The axon initial segment (AIS) plays a role in the selective localization of tau in the axonal compartment. Thus, disruption in the AIS barrier may allow tau to diffuse freely back into the somatodendritic compartment and potentially lead to neurotoxicity. Here, we analyzed AISs using stereological methods and protein immunoblotting, and the localization of tau was assessed with immunofluorescence optical density measurements and protein immunoblotting. None of the outcome measurements assessed, including AIS structure, AIS protein levels, the distribution of tau in neurons of the hippocampus (HP), and total tau or phospho-tau protein levels were different in young, middle-, and old-age Fischer 344 rats. The outcome measurements assessed, including AIS structure, AIS protein levels, the distribution of tau in neurons of the hippocampus (HP), and total tau or phospho-tau protein levels were not different in young, middle-, and old-age Fischer 344 rats, with the exception of a small reduction in AIS volume and diameter in CA2 of aged animals. These data suggest that aging largely has no effect on these properties of the AIS or tau distribution, and thus, may not contribute directly to tau mislocalization.

Significance Statement: Aging is a primaryrisk-factor for AD, but the events duringaging that contribute to the development of disease are unknown. In healthy neurons, the tau protein is enriched in the axon, a distribution facilitated, at least in part, by the axon initial segment (AIS). Tau accumulation in the cell body due to disruption of the AIS barrier is potentially a contributing factor to AD pathogenesis.Very little is known about the effects of normal aging on AIS proteins or levels and localization of tau. Here, we report that there were no changes in the AIS or tau localization with increasing age in rats, suggesting disease-specific effects maydrive changes in these factors during ADpathogenesis.