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P3‐095: ADVANTAGES OF HIERARCHICAL MODELS FOR REGIONAL PET ANALYSES
Author(s) -
Martin Peter R.,
Weigand Stephen D.,
Josephs Keith A.,
Schwarz Christopher G.,
Whitwell Jennifer L.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.1451
Subject(s) - bonferroni correction , statistics , linear regression , false discovery rate , statistical power , sample size determination , multiple comparisons problem , context (archaeology) , mathematics , regression , multilevel model , regression analysis , geography , biochemistry , chemistry , archaeology , gene
Background: Tauopathies, including Alzheimer’s disease and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), display numerous pathologies beyond the neurofibrillary tangles that define this class of disease. Cortical and hippocampal atrophy, ventricular dilation, white matter degeneration, gliosis and frank neuronal loss occur concomitantly with tau pathology, culminating in cognitive deficits and behavioral changes. Although current models of tauopathy have replicated some of these features to varying degrees, there still persists a need for more advanced and comprehensive models that exhibit all these pathophysiological and behavioral phenotypes. Methods: We developed a rat model that overexpresses human 4R/2N tau carrying the FTDP-17 mutation, P301S, under the CaMKIIa neuronal promoter. This transgenic line, McGill-R-Tau-P301S, was characterized at multiple timepoints using various behavioral, biochemical, immunohistochemical and imaging techniques. Results: Disease-associated phosphorylation and conformation dependent tau immunoreactivity was observed throughout the hippocampus and neocortex from 3 months of age, and progressed in a temporospatial dependent manner. Neuronal loss, cortical thinning and extensive ventricular dilation were present by 18 months of age. In parallel, astrocytic activation and disorganization, as well as pervasive microglia proliferation were observed. Notably, microglia displayed both amoeboid and distinct rod-like microglia morphologies. Additionally, using electron microscopy, we observed axon and myelin degeneration and the occurrence of axonal ballooning. Cognitive decline was detected starting at 18 months of age: rats were impaired in novel object recognition memory, spatial learning and memory, contextual and cued fear conditioning, in the absence of motor deficits. Conclusions: The McGill-RTau-P301S rat is a novel model of tauopathy which recapitulates important pathophysiological and behavioral phenotypes associated with human tauopathies. Thus, this model represents a unique and very valuable tool for research in Alzheimer’s disease and other tauopathies.