Alzheimer’s Disease & Dementia

Biography

Biography: Tangui Maurice

Abstract

The sigma-1 receptor (S1R) is a ligand-operated molecular chaperone localized on endoplasmic reticulum (ER), mitochondria and plasma membranes. Its activation modulates IP3 receptor-dependent Ca2+ mobilizations, facilitates the activation of ER stress sensor proteins and kinase pathways. Under chronic activation, it also recomposes lipid domains in membranes, which are highly functionalized domains. Interestingly, the chaperone can be directly activated (or inactivated) by several classes of ligands. These S1R agonists are potent neuromodulatory and neuroprotective drugs in different neurodegenerative insults and pathologies (stroke, Alzheimer's disease (AD), Parkinson's disease, ALS…). We examine the involement of the S1R in AD pathology and validate selective or non-selective S1R agonists as neuroprotective agents. First, we analyzed the impact of S1R invalidation (using S1R KO mice) on the vulnerability to AD pathology. Two main AD models were used, a nontransgenic model by direct icv injection of oligomeric amyloid- (A) protein fragments [25-35] (A25-35) in mice and transgenic lines overexpressing hAPPSwe or hAPPSweInd. We observed that AD toxicity and behavioral deficits are significantly amplified in S1R KO mice injected with A25-35 and in S1R KO x hAPPm lines. Second, we showed the protective potency of S1R agonists and mixed muscarinic/S1R ligands in AD models. The pathology was analyzed in terms of ER and oxidative stress, inflammation, mitochondrial damage, cell loss, memory deficits, increased APP processing and Tau hyperphosphorylation. We therefore confirmed the role of endogenous neuroprotection system in neurodegenerative processes and identified S1R agonists as potent neuroprotective and putatively disease-modifying agents.