Sporadic Alzheimer disease (sAD) is a neurodegenerative disorder that leads to acute memory and cognition loss in the elderly patients. An important characteristic of sAD is the diverse clinical sub-types that arise from different pathological phenotypes. Determining the molecular underpinnings of such clinical differences is important for diagnostic and therapeutic advances, but has remained a major challenge. Emerging evidence indicates that structural polymorphism within A? aggregates may cause the observed phenotypes in sAD. However, the relation between the neurotoxic, low molecular weight oligomers of amyloid- ? (A?) peptides and the observed phenotypes remains unclear. Results from our labs suggest that neurotoxic oligomers of A?42 formed in the presence of lipids (LDs) faithfully propagate their mesoscopic structure towards morphologically distinct fibrils and selectively induce vascular phenotype in transgenic AD mice. These results suggest that the distinct phenotypes can emerge from specific oligomer conformations, but also raise the question of whether LDs play a key catalytic role in generating distinct oligomer strains that manifest in pathology. We hypothesize that the physiochemical characteristics of LDs modulate A? aggregation to generate oligomer strains that propagate to elicit discrete phenotypes in the brain. The proposed research will focus on testing this hypothesis by determining the mechanistic understanding of LD-derived oligomer strains with three specific aims:
Aim 1 we will focus on understanding the molecular mechanisms that dictate LD- induced oligomer strain generation;
Aim 2 will focus on identifying the structures of LD-derived oligomers and how they relate to their propagation propensities, and Aim 3 will focus on determining how LD-oligomers induce phenotypes in mice brains. This project will involve a collaborative effort with biophysical and biochemical aspects investigated in the PI's lab, structural and mechanistic aspects in the Ramamoorthy lab (University of Michigan), molecular modeling work in the Hansmann lab (University of Oklahoma) and animal modeling work in the Levites lab (University of Florida). Together, the proposed research will generate critical insights into how phenotypes emanate from conformations of aggregates in sAD, and open new avenues for potential therapeutic interventions.
Sporadic Alzheimer disease (sAD) is a fatal neurodegenerative disorder that leads to acute memory and cognition loss in the elderly. Currently more than 5.5 million people in the US alone are affected by this devastating disease and the number is projected to almost triple by 2050, putting enormous pressure on the patients, caregivers and the economy. According to the CDC, death rates from AD dramatically climbed 55% between 1999 and 2014, making viable diagnostic and therapeutic avenues a critical need. The proposed project is focused on biochemically identifying the link between the molecular agents responsible for the acute loss of neurons in the brains of patients and many different pathological variations in AD such as early onset, rapidly progressing forms etc. Such establishment of the links between pathological outcomes and molecular markers responsible will facilitate a better understanding of the pathology, which will pave a way for diagnostic and therapeutic options for AD.
