Olfaction and Neurogenesis

The role of olfactory dysfunction and altered neurogenesis in neurogenerative diseases

The prevalence of age-related neurodegenerative disorders is increasing dramatically as people live longer and now affects millions of people worldwide. Due to this sharp increase, the total costs associated with dementia over the next 30 years is predicted to cost billions of dollars in Canada alone. At the present time there are no effective therapies, and there is a lack of affordable, expeditive biomarkers to predict and/or monitor disease progression. Furthermore, it is becoming increasingly evident that physicians need practical clinical tools that integrate knowledge across multiple domains of function in order to make evidence based personal decisions for their patients. Olfactory dysfunction and altered neurogenesis are observed in several neurological disorders including Alzheimer, Parkinson and Huntington disease. These deficits occur early in the phenotype and correlate with global cognitive performance, depression and degeneration of olfactory regions in the brain. These data suggest that olfactory dysfunction is a potential biomarker of future cognitive impairment and may be useful as an endpoint in clinical or murine neurodegenerative therapeutic trials. The overall goal of our research is to establish if olfactory dysfunction accurately predicts impending cognitive decline in humans and to determine the underlying mechanism(s) responsible in order to define novel therapeutic approaches for neurodegenerative diseases. Identification of biomarkers will contribute substantially to our understanding of the pathogenesis of the disease and brain-behaviour relationships, and enable assessment of the efficacy of putative therapies. The end result will be integration of knowledge generated into clinical practice.

The sense of smell, and the process by which new nerve cells are formed (neurogenesis), are known to be altered in several neurological disorders such as Huntington (HD), Alzheimer and Parkinson disease. One of the regions in the brain where new nerve cells are formed is called the subventricular zone. Normally, the new neurons made in that zone migrate to the olfactory bulb ̶ a specialized structure involved in our sense of smell. Evidence demonstrates that deficits in the sense of smell and neurogenesis occur early in neurodegenerative diseases. These tell-tale deficits are important to understand as they are closely connected with depression and cognition i.e. the mental processes that affect working memory, comprehension, reasoning and decision making. An altered sense of smell could very well turn out to be a predictor of future cognitive impairment and may be useful as an endpoint in neurodegenerative clinical trials.

Despite evidence demonstrating early problems with olfaction in HD patients, only limited details are available in HD models. Our research demonstrates that atrophy and cell death of neurons are observed in specific olfactory regions of the brain in HD mouse models. Furthermore, deficits in odour investigative behaviour are observed in the HD mice. We want to determine whether this nerve cell death is associated with smell dysfunction and altered neurogenesis at the molecular level. In order to determine whether alterations in cell death pathways (apoptotis) are associated with the olfactory dysfunction and altered neurogenesis in HD we are assessing caspase activation pathways in olfactory regions of the brain. When the caspase cuts other proteins, protein fragments are generated that can then be involved in triggering dysfunction in the cell. Exploring the role of caspases in human olfactory brain regions, and in models that mimic key features of the disease seen in humans, will help to develop successful treatments to slow or prevent the behavioral deficits and nerve cell atrophy observed in HD.

Le rôle de la dysfonction olfactive et la neurogenèse dans les maladies neurodégénératives

Avec l’augmentation de la durée de vie, l’incidence des maladies neurodégénératives s’accentue de façon importante. Ces affections touchent maintenant des millions de personne. En raison de cette forte hausse, les coûts totaux associés à la démence au cours des 30 prochaines années coûtera milliard du dollar au Canada. À l'heure actuelle, il n'y a pas de traitements efficaces, de même qu’il existe un manque au niveau des biomarqueurs expéditifs et abordables pour prédire et/ou surveiller la progression de la maladie. En outre, il devient de plus en plus évident que les médecins ont besoin d'outils cliniques pratiques qui intègrent les connaissances à travers de multiples domaines afin de prendre des décisions personnelles fondées sur des preuves pour leurs patients. La dysfonction olfactive est observée dans plusieurs maladies neurologiques, y compris la maladie d'Alzheimer, la maladie de Parkinson et la maladie de Huntington. Ces déficits se produisent au début de la maladie et corrèlent avec la performance cognitive globale, la dépression et la dégénérescence des régions olfactives dans le cerveau. Ces données suggèrent que la dysfonction olfactive est un biomarqueur potentiel de la future déficience cognitive et serait utile en tant que critère clinique dans les essais thérapeutiques. L'objectif global de notre recherche est d'établir si la dysfonction olfactive prédit avec précision le déclin cognitif imminent chez l'homme et de déterminer le (s) mécanisme (s) sous-jacent (s) responsable (s) afin de définir de nouvelles approches thérapeutiques pour les maladies neurodégénératives. Le résultat final sera l'intégration des connaissances générées dans la pratique clinique