Neurobiology of Alzheimer's disease: risk markers, prognosis and therapeutic response

Abstract

Since 1997, with the support of two Projetos Temáticos granted by FAPESP, our laboratory has been performing translational research applied to the analysis of the membrane phospholipids abnormalities, with a special focus on its influence in brain homeostasis and its downstream impact in neuropsychiatric diseases. In this new project, multiple biological mechanisms related to the pathophysiology of Alzheimer disease (AD) will be evaluated, in a search for clinical correlates of the higher risk of dementia in elderly patients with cognitive and mood disorders. This multidisciplinary project is divided in two modules: in module 1 (Clinical, Laboratorial and Neuroimaging studies), biological markers that influence risk, clinical course and therapeutic response will be determined after investigating DNA polymorphisms, biomarkers in the cerebro-spinal fluid and peripheral blood, as well as structural and functional brain imaging using MRS and PET. Our main goal is to establish tools for an early diagnosis of AD and to evaluate the effectiveness of pharmacological and no pharmacological interventions in reducing of cognitive impairment, with the final aim of preventing the establishment of dementia. In module 2 (Neurochemistry and Molecular Biology), in vitro (primary neuronal cultures) and in vivo (transgenic mice that accumulate beta-amyloid, Aβ, within the brain) experimental models will be used to study the inter-related molecular mechanisms involved in the pathogenesis of AD. Aβ ¬toxicity will be investigated with a focus on its impact over neurogenesis, enzymatic activity and gene expression. Due to its neurotrophic and neuroprotective activities, the capability of lithium to modulate these processes will be investigated in pre-clinical models, amalgamating all experimental and clinical aspects of this project. (AU)