Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration

Figure 2

Proposed model through which chronic stress and glucocorticoids (GCs) may contribute to Alzheimer disease (AD) pathology. The model illustrates how chronic stress and high GC levels can trigger AD pathology; the figure is based on experimental evidence obtained in cellular and animal models of AD. Extended exposure to stress/high GC levels activates the amyloidogenic pathway of amyloid precursor protein (APP). This so-called misprocessing of APP involves the sequential cleavage of APP by β- and γ-secretases, resulting in the generation of toxic amyloid β (Aβ). Subsequently, the cytoskeletal protein Tau, which is mainly localized in axons (red in the representation of a healthy neuron), becomes aberrantly hyperphosphorylated, catalyzed by glycogen synthase kinase (GSK3β) and/or cyclin-dependent kinase 5 (CDK5). Hyperphosphorylated Tau is trafficked to, and accumulates in, the somatodendritic compartment, where it oligomerizes and forms insoluble aggregates (red in the diseased neuron). In addition, the abnormal conformation adopted by Tau and caspase 3-mediated truncation of Tau is accompanied by dysregulation of the molecular chaperones Hsp90 and Hsp70, which normally serve to promote Tau degradation (left panel). This cascade of events causes neuronal atrophy and loss, followed by cognitive impairments.