Skip to main content

Spine plasticity in changing environment and diseases

Final Report Summary - SPICED (Spine plasticity in changing environment and diseases)

Glucocorticoids (GC) are the class of drugs most widely prescribed worldwide in current use for treatment of inflammatory-related diseases. Administration at high doses is a mainstay of treatment for numerous neuroinflammatory illnesses. Yet, GC therapy is often accompanied with severe side effects (neurodegeneration, psychosis, cognitive impairment, mood instability...) associated with poor comfort during the disability-adjusted life years. This is because the GC receptors (GR) are expressed virtually in all cells and organs for influencing physiological processes that are manifold.
In view of its widespread uses in the clinic it comes to a surprise that the mechanisms essential for the efficacy of GC, the endogenous and therapeutic, are still poorly understood. Contrary to the classic view, neuroinflammation can establish persistently even in patients featuring high levels of GC circulating in blood (hypercortisolism). Worst is that hypercortisolism exaggerates neuro-inflammatory signals that interact with disease mechanisms. It would appear counterintuitive that enhanced susceptibility to diseases with inflammatory component is linked to hypercortisolism.
The ISSUE is that GC can potentiate neuroinflammatory processes despite their potent anti-inflammatory activity. This is an important issue in clinical practice given that treatment with GC cause side effects and significant economic burden and for the families.
One EXPLANATION to consider is GC resistance coined for the loss of tissue sensitivity or response to GC that causes severe health issues linked to chronic stress in millions of people worldwide. GC resistance is a postulated risk factor for accelerating the onset and severity of neurodegenerative and neuropsychiatric diseases, which have in common a neuroinflammatory component and hypercotisolism. Molecular and cellular mechanisms of GC resistance in the brain have remained unknown and are putative therapeutic targets.
Our PRELIMINARY DATA identified gatekeeper mutations in GR that cause insufficient GR functions. These mutations target phosphorylation sites responding to a member of the Nerve Growth Factor (NGF) family, Brain-Derived Neurotrophic Factor (BDNF).
Our WORKING MODEL is that BDNF acts as permissive signal to unlock GR full-antiinflammatory functions.
Our WORKING HYPOTHESIS is that deletion of the BDNF-sensitive phosphorylation sites could cause GC resistance and enhance susceptibility to diseases with an inflammatory component. Alzheimer’s disease (AD) and major depression (MDD), which have distinct etiologies but common neuroinflammatory response associated with chronic hypercortisolism belong to the spectrum of disorders that could benefit from the relief of GC resistance. It concerns 80% of MMD patients highlighting the urgency of the issue.
Our STRATEGY is complementary with AD research, targeting senile plaques or neurofibrillary tangles, and with MDD research, developing fast-acting antidepressant drugs. It consists to deconstruct the link between GC resistance and BDNF in mouse models of AD and MDD.
Strategies to alleviate GC resistance are innovative, addressing a significant knowledge gap in the pathophysiologies and treatment of disorders caused by stress.
With the increased life expectancy in modern societies the number of people affected by stress-induced chronic diseases is increasing and so the cost of treatment. In these circumstances, the management of disability-adjusted life years should be a priority. Our study fits with the ANR mission because discoveries will have broad impact extending beyond AD and MDD for the benefit of autoimmune, inflammatory and cerebrovascular diseases. It is designed as preclinical studies in mouse models to help modify disease trajectories and increase comfort during the disability-adjusted life years. This can be done by alleviating GC resistance to achieve full GC anti-inflammatory responsiveness with fewer side effects.