Grant: Project Grant

The beginnings of Alzheimer's Disease occur in a group of cells in the brainstem that produce noradrenaline. This group is called the locus coeruleus. The first brain changes in humans appear quite early as production of abnormal tau protein by these cells. The abnormal tau spreads from locus coeruleus along memory pathways until reaching the cortex and becoming tangles. Abnormal tau in locus coeruleus cells occurs early in our lives and is seen in most by age 30, but its effects are not noticeable and spread occurs over decades. We need to detect and prevent these early events. Our evidence suggests distinguishing between very similar patterns is helped by the locus coeruleus. We will test this idea by producing abnormal human tau in rat locus coeruleus cells and testing similar odor discrimination ability. We know the locus coeruleus is activated by new, and by stressful, experiences. Importantly, it is activated differently by these two experiences. We think novel experience activation will slow abnormal brain changes, while stress will increase their rate and extent. We will activate rat locus coeruleus cells containing abnormal tau to mimic either novel and enriched or stressful experience. We predict the spread of abnormal tau along memory pathways will be fast with stress patterns and slow, or prevented by, novelty patterns that can promote learning and memory. Locus coeruleus may be a two-edged sword in Alzheimer's Disease acting either to diminish or accelerate the later likelihood of Alzheimer's Disease appearing. We will identify activity patterns that decrease, or increase, the spread of the earliest brain changes and we will relate their occurrence to pattern discrimination ability to provide new ideas for detecting early locus coeruleus changes and for designing lifestyles to prevent the spread and expression of abnormality, thus stopping later Alzheimer's Disease.