Prot. 2022ZSC4Z5 - TARGETING SIGMA-1 RECEPTORS TO TREAT COGNITIVE DYSFUNCTION INDUCED BY NORADRENERGIC LOSS

Loss of noradrenaline (NA)-producing locus coeruleus (LC) neurons is an early and prominent feature of Alzheimer's disease (AD), but the reason for such vulnerability is yet unclear. Recent advances in AD biomarker research have linked LC cell loss to oxidative stress, implying that promotion of anti-oxidant responses, by preventing LC degeneration, would also ameliorate AD-related pathology. We have recently shown that activation of Sigma-1 receptors, mainly expressed in brain regions closely related to cognition, exerts anti-amnesic and neuroprotective actions in rat models of mild or severe memory loss. However, what links cognitive deficits to oxidative stress, NA loss and tissue pathology is still unclear. The present proposal brings together scientists with complementary expertise in modeling CNS dysfunction in rodent and cellular paradigms, in medicinal chemistry, drug design and discovery. We plan to use the TgF344 rat, a well-established transgenic rat model recapitulating several histopathological and cognitive AD features of early and late memory dysfunction, in association with varying degrees of experimentally-induced NA loss. In this transgenic model we will determine the effects of bi-functional anti-oxidant sigma-1 receptor (S1R) agonists on AD-like cognitive deficits and tissue pathology. One of such compounds is already available to the consortium, whereas others already developed or under development will be possibly screened during the conduction of the studies and tested for their biological activity. High quality histological, neurochemical and imaging end-points will thus be evaluated by using a variety of techniques allowing to determine the cause-effect relationship among oxidative stress, neurodegeneration and memory loss. Moreover, the effects of bifunctional SR1 agonists will be investigated in neuronal and glial cell types to evaluate their impact on cellular redox state, cell viability and myelination using omic technologies based on image and transcriptome analyses. In addition to the obvious knowledge advancements on the relationships between oxidative stress, LC degeneration, tissue pathology and memory loss, the studies may contribute to set a basis for NA- and/or bi-functional Sigma1 R agonist-based AD therapies.

Loss of noradrenaline (NA)-producing locus coeruleus (LC) neurons is an early and prominent feature of Alzheimer's disease (AD), but the reason for such vulnerability is yet unclear. Recent advances in AD biomarker research have linked LC cell loss to oxidative stress, implying that promotion of anti-oxidant responses, by preventing LC degeneration, would also ameliorate AD-related pathology. We have recently shown that activation of Sigma-1 receptors, mainly expressed in brain regions closely related to cognition, exerts anti-amnesic and neuroprotective actions in rat models of mild or severe memory loss. However, what links cognitive deficits to oxidative stress, NA loss and tissue pathology is still unclear. The present proposal brings together scientists with complementary expertise in modeling CNS dysfunction in rodent and cellular paradigms, in medicinal chemistry, drug design and discovery. We plan to use the TgF344 rat, a well-established transgenic rat model recapitulating several histopathological and cognitive AD features of early and late memory dysfunction, in association with varying degrees of experimentally-induced NA loss. In this transgenic model we will determine the effects of bi-functional anti-oxidant sigma-1 receptor (S1R) agonists on AD-like cognitive deficits and tissue pathology. One of such compounds is already available to the consortium, whereas others already developed or under development will be possibly screened during the conduction of the studies and tested for their biological activity. High quality histological, neurochemical and imaging end-points will thus be evaluated by using a variety of techniques allowing to determine the cause-effect relationship among oxidative stress, neurodegeneration and memory loss. Moreover, the effects of bifunctional SR1 agonists will be investigated in neuronal and glial cell types to evaluate their impact on cellular redox state, cell viability and myelination using omic technologies based on image and transcriptome analyses. In addition to the obvious knowledge advancements on the relationships between oxidative stress, LC degeneration, tissue pathology and memory loss, the studies may contribute to set a basis for NA- and/or bi-functional Sigma1 R agonist-based AD therapies.