Traumatic axonopathy and Alzheimer tau propagation

点击翻译按钮获取中文摘要

PROJECT SUMMARY In this application we explore the role of axonal injury in the propagation of protein aggregates in the CNS, based on the known association between traumatic brain injury (TBI) and neurodegenerative disease. Emphasis here is on the microtubule-associated protein tau, which undergoes a number of modifications and then aggregates in hallmark deposits in the so-called tauopathies, neurodegenerative diseases that include Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Specifically, we propose that axonal pathology and tauopathy interact and that the integrity of CNS axons is a key independent factor influencing propagation of tau hyperphosphorylation or aggregation across interconnected brain regions. Our proposal is founded on pilot data confirming findings from other groups that we can generate extensive tauopathy in forebrain and some brainstem circuits after injections of fibrillar tau extracted from AD brains (AD-tau) in cortex and hippocampus. More importantly, we have recently established the role of sterile alpha and HEAT/Armadillo motif containing 1 (SARM1), the main trigger of Wallerian axonal degeneration, as a key instructive signal for traumatic axonal breakdown in the CNS and identified small CNS-penetrant molecules that may interfere with SARM1-related signaling. Our proposal is organized in two specific aims. In Aim 1 we explore whether traumatic axonal injury, by degrading axon structure, accelerates/expands the tauopathy induced by seeding the mouse brain with AD- tau to form pathological (hyperphosphorylated/aggregated) tau signatures in host brain circuits. Here we propose that axonal injury caused by the central fluid percussion model of diffuse TBI will facilitate the propagation of tau pathology in mice inoculated in the hippocampus and neocortex with tau seeds extracted from AD brains. In Aim 2 we explore the role of the axonal degeneration signal SARM1 in the systems propagation of tau pathology away from the initial AD-tau inoculation sites and in the related neuroinflammation. Here we propose that by deleting SARM1, thus protecting axons in the same diffuse TBI model as Aim 1, we may ameliorate the severity and spread of baseline or injury-accentuated tauopathy and the related neuroinflammation and, eventually, suppress neurodegeneration/cell death. To achieve the previous aims, we use a complement of anatomical and genetic tools including SARM1 knockout mice and high-resolution neuropathology including, among else, brain clearing methodologies such as CLARITY and SHIELD and electron microscopy. Once we establish SARM1 as a relevant molecular target in tauopathy, then we will be in position to confirm these findings with more precise gene editing using CRISPR methodologies available in our lab and small molecules that interfere with SARM1 signaling. In concert, by exploring the role of SARM1 in the propagation of aggregation-prone or aggregated tau, we pursue a new approach in understanding the mechanisms of neurodegenerative tauopathies, including AD and CTE. Because SARM1-related signaling may be soon tackled with small molecules, we also identify molecular targets with substantial therapeutic potential.