Abstract
Glucocorticoid resistance is a risk factor for Alzheimer’s disease (AD). Molecular and cellular mechanisms of glucocorticoid resistance in the brain have remained unknown and are potential therapeutic targets. Phosphorylation of glucocorticoid receptors (GR) by brain-derived neurotrophic factor (BDNF) signaling integrates both pathways for remodeling synaptic structure and plasticity. The goal of this study is to test the role of the BDNF-dependent pathway on glucocorticoid signaling in a mouse model of glucocorticoid resistance. We report that deletion of GR phosphorylation at BDNF-responding sites and downstream signaling via the MAPK-phosphatase DUSP1 triggers tau phosphorylation and dendritic spine atrophy in mouse cortex. In human cortex, DUSP1 protein expression correlates with tau phosphorylation, synaptic defects and cognitive decline in subjects diagnosed with AD. These findings provide evidence for a causal role of BDNF-dependent GR signaling in tau neuropathology and indicate that DUSP1 is a potential target for therapeutic interventions.
Highlights
Stress is a major risk factor for promoting or aggravating neuropathological changes within the cortico-limbic system in neuropsychiatric, neurodegenerative and metabolic disorders[1,2,3]
Induction of DUSP1 (Dual Specificity Phosphatase-1/mkp1), EGR1 (Early Growth Response-1), NR4A1 (Nuclear Receptor subfamily-4 Group-A member-1/nur77/NGF1A), P11 (S100A10) and FOS (FBJ Osteosarcoma viral Oncogene homolog/AP1) in primary cortical neurons responded to co-stimulation with brain-derived neurotrophic factor (BDNF) and dexamethasone (Fig. 1B), but only DUSP1 and NR4A1 required glucocorticoid receptors (GR) phosphorylation at BDNF responsive sites to synthesize the protein product (Fig. 1C)
Hypersecretion of glucocorticoids is a risk factor for accelerating neuropathological changes associated with Alzheimer’s disease (AD) in humans and in relevant AD animal models[38,39]
Summary
Stress is a major risk factor for promoting or aggravating neuropathological changes within the cortico-limbic system in neuropsychiatric, neurodegenerative and metabolic disorders[1,2,3]. Neurobiological correlates of glucocorticoid plasticity consist in epigenetic modifications, mitochondrial function and cytoskeletal remodeling based on changes in phosphorylation of signaling and structural proteins[10,11]. Stress and glucocorticoids change the expression and activity of tau kinases, suggesting that neuropathology induced by cumulative stress occurs via abnormal phosphorylation waves and gene transcription[13,15]. GR is a central pivot of glucocorticoid responses at the intersection of multiple signaling pathways for stress/ depression systems, cognitive functions, and synaptic plasticity, notably the growth factor signaling pathways[22,23]. We propose a novel mechanism to explain how glucocorticoid activities can change from beneficial to detrimental It relies on the context at exposure, if BDNF signaling is ‘ON’ or ‘OFF’ at the time of glucocorticoid stimulation to produce a unique response It relies on the context at exposure, if BDNF signaling is ‘ON’ or ‘OFF’ at the time of glucocorticoid stimulation to produce a unique response (for review see ref. 23)
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