Understanding Amyloid Pathology - Multiomic Activity Imaging of Plaque Formation Dynamics (AmyMAP)

Alzheimer’s disease (AD) is an incurable brain disorder that currently debilitates more than five million people in the United States alone. Clinically, AD typically presents as a slow and progressive decline in cognitive performance that inevitably culminates in severe dementia. Currently AD can only be positively confirmed postmortem by dementia with amyloid beta (Aβ) peptides plaques and neurofibrillary tangles containing the hyper-phosphorylated Tau protein. It is generally accepted that plaques and tangles play important and complex roles in AD. The prevailing model of AD pathogenesis has been that changes in Aβ metabolism precipitate a damaging cascade upstream of tau pathology and eventual neurodegeneration. However, there is a lot about these enigmatic pathological marks that we do not understand. The relevance of Aβ and amyloid plaques in AD has seen a recent resurgence in FDA approvals and activities. For example, the FDA recently approved aducanumab that can remove amyloid plaques as measured by positron-emission tomography. Although the importance of the amyloid plaques in AD have long been recognized, exactly how plaques develop over time, the extent of their diversity, and their relation to toxicity or homeostatic response of the surrounding neuronal circuits remains unclear. Therefore, it is of great importance to map the trajectory of distinct classes of amyloid aggregates during the early stages of A pathology. We have recently discovered several important and early events in the formation of Aplaques inAD model brains and have developed several new approaches to study these processes. First, we discovered that impaired protein homeostasis in axon terminals represents a pioneering synaptic defect in amyloid model mice. Second, we found that the synaptic vesicle release and recycling machinery has selectively hampered turnover through plaque dependent and independent mechanisms. Third, formation of structurally distinct plaques are associated with differential Aβ peptide deposition. Finally, Aβ42 comprises the initial core structure followed by radial outgrowth and later incorporation of Aβ38. To rigorously extend these findings, in Aim 1 we will obtain a dynamic map of amyloid plaque pathology in mouse model brains during aging. The goal of Aim 2 is to determine how the AD risk factor Trem2 influences A and lipid dynamics at amyloid plaques. In Aim 3, we will integrate the multi-omic amyloid maps with measures of altered synaptic communication and neurotoxicity. Finally, in Aim 4, we apply knowledge gained above in a practical manner with 3D mapping for the neuroscience research community. The proposed research will advance our understanding of AD by determining when Aβ is aggregating in the extracellular space, what structural Aβ assemblies are formed, and how these oligomers and plaques trigger mechanisms leading to downstream synaptic dysfunction.