Project 3: Role of Inflammation on Induction of Tau Pathology in the Brains of Transgenic Mice The Alzheimer disease (AD) brain is characterized by two types of protein aggregates, neurofibrillary tangles and amyloid plaques, which are found predominantly in the hippocampus, amygdala, and cortex. The buildup of Bamyloid (AB) and tau pathology is believed to directly cause or contribute to the progressive cognitive deficits. Because APP and/or presenilin mutant transgenic mice do not develop neurofibrillary pathology despite extensive plaque deposition, the introduction of multiple transgenes into the mouse germline is required to produce both hallmark lesions in mice. My lab recently derived a triple transgenic model of AD (3xTg-AD) in which both plaques and tangles develop in AD-relevant brain regions. The mice were derived by co-injecting human APPswe and tauP301L transgenes, both under the control of the Thyl.2 regulatory element, into single cell embryos harvested from PS1M146V homozygous knockin mice. The mice generated via this strategy are on the same genetic background (thereby avoiding an important confounding variable), breed efficiently (as easily as a single transgenic strain), and exist in both a hemizygous and homozygous genotype (allowing one to assess the effects of doubling gene expression on cognition in mice of the same genetic background). The 3xTg-AD mice represent a critical new resource for understanding the relationship between AB and tau interactions. Preliminary data from our laboratory show that AB can directly affect the tau pathology, as genetic or pharmacological approaches that modulate AB levels have a direct effect on tau pathology. In contrast, modulating tau levels through genetic or pharmacological means does not appear to significantly affect AB pathology. The sum of these studies indicates that AB lies upstream of tau in the pathogenic cascade. The primary focus of this grant application is to better elucidate the pathways by which AB modulates tau pathology in the 3xTg-AD mice. Although evidence from our laboratory indicates that AB likely affects tau pathology through several different mechanisms, one of the key pathways appears to involve microglial-mediated inflammation. Here we propose to elucidate the immune mediated mechanisms by which AB modulates tau pathology.
Four specific aims are proposed:
Aim 1 will determine the role that microglia play in the induction of the tau pathology.
Aim 2 will investigate the role of inflammation in mice with advanced neuropathology and whether it exacerbates or ameliorates the pathology.
Aim 3 proposes to use a genetic or pharmacologic approach to selectively increase IL1 levels in the brains of the 3xTg-AD mice to test the hypothesis that IL1 is a potent mediator that increases the severity of plaques and tangles. The last aim proposes to determine the effect that cerebral amyloid angiopathy has on inflammation, and focuses on crossing the 3xTg-AD mice to the ApoE3 and ApoE4 knockin mice.
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|Krotee, Pascal; Rodriguez, Jose A; Sawaya, Michael R et al. (2017) Atomic structures of fibrillar segments of hIAPP suggest tightly mated ?-sheets are important for cytotoxicity. Elife 6:|
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