Project 2: Synergy of ABeta clearance mechanisms in vivo

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Accumulation of Aβ peptide in the brain appears to initiate disease onset and causes of many of the cognitive and behavioral symptoms related to Alzheimer’s disease (AD). Other pathologies such as hyperphosphorylated tau as neurofibrillary tangles and α-synuclein (α-syn) as Lewy Bodies are also detrimental in AD. While Lewy Bodies are best known for accumulation within the striatum in Parkinson’s disease, similar structures also composed of α-syn are present in 60% of AD cases. Given that Aβ and α-syn pathologies often co-exist, our goal is to understand the complex biology of both peptides and how they interact to influence the development and progression of AD. Aβ is normally produced in neurons and secreted into the brain extracellular fluid, or interstitial fluid (ISF), which is one source of Aβ that forms oligomers and plaques. Conversion of Aβ from its normal soluble form into these toxic conformations is concentrationdependent; high levels of Aβ are much more prone to aggregate than lower concentrations of Aβ. A balance between Aβ generation and elimination determines the steady-state concentration of Aβ in the brain. Aβ levels rise dramatically in AD, suggesting that at least one of these metabolic processes is disrupted in the diseased brain. Recent studies strongly suggests that a key factor leading to Aβ accumulation in the AD brain is a defect in clearing the peptide from the brain. Several mechanisms involved in active Aβ clearance from the brain have been identified, such as 1) proteolytic degradation, 2) cellular uptake, and 3) active transport across the bloodbrain barrier. While these clearance pathways work simultaneously to remove Aβ from the brain, the degree to which each mechanism works independently, competes, or cooperates remains unclear. Many studies have focused on how each of these mechanisms individually clear Aβ, however few have determined how these mechanisms work in synergy. Interestingly, some of these clearance pathways appear to act on Aβ as well as α-synuclein. Overall, we hypothesize that clearance of Aβ and α-syn does not occur in isolation, but instead is influenced by an array of mechanisms as well as by each other. We will identify how these pathways interact to clear Aβ from the brain by blocking one or more mechanism at a time and measuring the rate of Aβ clearance from the ISF. We will also determine differences in function of these clearance pathways in settings of combined pathology (α-syn and Aβ).