Hormone-related aging and dementia – GRAND

Developmental deficits in cognitive function and dementia create a high medical, emotional and economic burden for society. Over 25 million people suffer from dementia worldwide; with one new case diagnosed every 7 seconds. On the other end of the age spectrum, 3-8% children in Europe and USA suffer from neurodevelopmental cognitive disorders. Intriguingly, evidence suggests that there is a gendered aspect to the predisposition for cognitive deficits, dementia and ageing dependent decline such as Alzheimer’s disease (AD), the women being more at risk to develop AD than men after menopause. Conversely, the ability to undergo puberty and become fertile is also affected in some of diseases associating cognitive deficits and early onset of AD (e.g., Down Syndrome –DS-). Equally intriguing is the fact that several disorders that are characterized by dementia also have a second component, acquired anosmia or the gradual loss of odor detection (e.g.,–DS- and Alzheimer diseases –AD), suggesting that the processes that underlie various phenotypes are linked. An intriguing candidate, whose absence could mediate all of these processes, is a fertility hormone. Despite evidence to suggest that neuron function secreting this hormone, which markedly differs between sexes, plays a role in aging, very little is known about the mechanism by which these cells might regulate age-related cognitive decline and dementia. As a proof of concept, our preliminary data indicate that olfactory and cognitive deficits displayed by mutant mice models can be rescued by intracerebral grafts of these neurons.
The overall objective of this proposal is therefore to explore the putative causal link between brain hormone signaling and cognition from the perinatal period to old ages. Anosmia and hormone deficiency may be associated to cognitive changes and dementia. We will explore this hypothesis using three rodent models: Ts65Dn mice that model DS and AD, mice that lose hormone expression during postnatal development or shelter impaired hormone neuronal activity, and a naturally occurring mouse line that displays a phenotype of accelerated aging (Senescence Accelerated Mouse-Prone 8; SAMP8). To this end, we have assembled the “GRAND” consortium to i) understand how hormone affects the development and ageing of a functional circuitry in the neuroendocrine-cognitive network (Aim 1), ii) investigate the role of hormone in odor perception and olfactory bulb, cortical and hippocampal electrophysiological activities (Aim 2), iii) to analyze hormone network activity during neonatal development and ageing (Aim 3) and iv) investigate if neuronal network activity, cognitive performance, anosmia and age-related expression of AD-related proteins can be rescued by hormonal replacement using pharmacological therapy (hormonal treatment), gene therapy (viral infection) or cell therapy (neuronal grafting) (Aim 4). To carry out this innovative project in a highly competitive field of neuroscience, we have assembled an interdisciplinary and team consisting of internationally renowned leaders with an admirable track record in the field of Neuroscience, Neuroendocrinology (Partner 1: Vincent Prévot & Partner 3: Philippe Ciofi) and Neurodegenerative Diseases (Partner 2: Luc Buée).
We are convinced that the success of the proposed research plan will have important implications for public health by providing original insight in the mechanism by which mental retardation, cognitive decline and dementia co-segregate with anosmia and determine whether hormone deficiency could be an underlying cause for these disorders.
Finally this project has clear foreseeable translational impact with the potential to be adapted for clinical use, using hormone agonists to add other indications such as dementia or the improvement of cognitive function in Down syndrome patients.