Project 1: Intracellular amyloid accumulation, innate immunity and pathogenesis. Project 1 proposes that the accumulation of intracellular """"""""amyloid"""""""" contributes to pathogenesis by activating an innate inflammatory cascade that represents a futile attempt to degrade or eliminate this amyloid by activating autophagy and ultimately leading to neuronal death and the initiation of a neuritic plaque. Project 1 examines the contribution of two unique types of amyloid immunoreactivity to aging and AD through this inflammatory mechanism and it explores the potential role of late onset AD genes in this process. One type of unique amyloid involves the dramatic accumulation of amyloid fibril monoclonal (M78) immunoreactivity in nuclei in human and Tg mouse brain, which is correlated with intraneuronal nuclear accumulation of APP immunoreactivity. The nuclear amyloid immunoreactivity is specifically associated with eariy plaque pathology (stage A or B) in humans and at 12 months in 3xTg-AD transgenic mice. The staining is reduced or absent in late stage AD and at later times in transgenic mice. The other type of unique amyloid is specifically associated with subset of vascular amyloid. Confocal immunofluorescence indicates that the M31 immunoreactive vascular amyloid accumulates at least partially intracellularly in vascular smooth muscle cells. The goals of project 1 are to test the hypothesis that the accumulation of the amyloids represent an """"""""infection"""""""" of the cell with a prion like agent that is associated with activation of the innate immune response.
Specific aim 1 will establish the fundamental characteristics of the accumulation of these unique types of amyloid and test the hypothesis that their accumulation is associated with leakage of lysosomal cathepsins and cystatin c into the cytosol and activation of the NLR infiammasome, resulting in the activation of caspase 1 leading to neuronal death by a mechanism related to """"""""NETosis"""""""".
Specific aim 2 will examine whether LOAD genes, PICALM, clusterin and TREM2, recentiy identified by GWAS play a role in the intracellular accumulation of the unique amyloids.
Specific aim 3 will explore whether these unique types of amyloid display fundamental properties of infectious agents, like prions and whether they can be propagated by """"""""seeding"""""""" to cells. We will determine whether the the phenotype of the infected cells matches the intracellular amyloid pathology in human brain. Dr. Glabe's project 1 will provide Dr. Cotman with oligomers. Project 1 will interact with Dr. LaFeria on intracellular APP and A in the 3XTg-AD mouse and AAV vectors and Dr. Cribbs on the accumulation of vascular amyloid. It will interact with Dr. Tenner on the role of Clq in neuritic plaque formation and the relationship of intraneuronal CRIto intraneuronal amyloid.
The critical problem that needs to be overcome for progress in the treatment of AD is a clear understanding of the mechanisms of pathogenesis the disease. Understanding'what is wrong is critical to developing strategies to prevent or cure the disease. We have discovered two novel types of intracellular amyloid fibril immunoreactivity in human and transgenic mouse brains. The goals of this project are to determine whether these novel subtypes of intracellular amyloid immunoreactivity are perceived by cells as an infectious agent, activating the innate immune response and ultimately neurodegeneration and AD.
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