Grant: Operating Grant

Our lab has contributed significantly towards the understanding of cellular and molecular aspects of the earliest stages of the Alzheimer's disease (AD) pathology through the generation of novel cell and transgenic animal models as well as studies in the human brain. An example of the latter is our paper "A paradoxical upregulation of glutamatergic presynaptic boutons during Mild Cognitive Impairment," (highlighted in Nature Clinical Practice Neurology). The present grant application is the natural continuation of these studies, aimed at responding to key questions related to the cellular and molecular pathology of this devastating disease. Questions such as: Is the paradoxical increase in cortical synaptic numbers at the early stages of AD a compensatory response or pathological event? Does the early pathological accumulation of toxic Abeta peptides unleash an inflammatory process? What is the molecular organization of these Abeta peptides which are lodged inside neurons in brain regions vulnerable to the AD pathology? Are these Abeta peptides responsible for the pre-amyloid-plaque inflammatory process? Will this pre-amyloid-plaque contribute to the dysregulation of the ERK/CREB pathway (a pathway affecting synaptic plasticity essential to memory formation)? Is this newly identified "pro-inflammatory" process also found in key brain areas of Mild Cognitive Impairment sufferers (MCI is a clinical stage preceding AD)? Is this pro-inflammatory process apparent and related to cognition before MCI and correlated with cognitive decline? These essential questions are formulated in a research plan under three guiding Hypotheses and will significantly contribute to our current understanding of the molecular and cellular events leading to brain dysfunction in the "twilight" region between the healthy brain and the start of AD. These investigations will render valuable clues for possible early therapies or prevention of AD.