Glucocorticoid hormone (cortisol) affects axonal transport in human cortex neurons but shows resistance in Alzheimer's disease

The changes of tissue sensitivity to glucocorticoids are associated with many pathological states including neurological diseases. In the present study, using a novel in vitro post‐mortem tracing method on human brain slices, we demonstrated that cortisol, a major glucocorticoid hormone in humans, affected axonal transport both in the cortex neurons in four Alzheimer's disease (AD) patients and four nondemented controls. Cortisol appeared to affect axonal transport of prefrontal cortex (PFC) and temporal cortex (TC) neurons in AD patients and controls in a dose‐dependent way at concentrations of 30, 60, 120 and 240 μg dl−1. Higher doses of cortisol were needed for TC neurons to achieve a similar axonal transport effect as obtained in PFC neurons in AD patients. The maximum effect (Emax) on axonal transport was achieved in PFC slices at relatively low contraction (30–120 μg dl−1), while in TC slices, a maximum effect was only reached at relatively high concentrations (120–240 μg dl−1). For PFC and TC slices from nondemented aging subjects, lower doses of cortisol (30–60 μg dl−1) on axonal transport were sufficient to achieve the maximum effect as compared to those used in AD brain slices, while levels of more than 60 μg dl−1 of cortisol mostly depressed axonal transport. These results suggest that glucocorticoid resistance, which is thought to contribute to the pathogenesis of a number of common human disorders, may exist in AD brains and play an important role in neuropathological mechanisms and dementia.