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P3‐085: FOCALLY INDUCED TAU PATHOLOGY IN APP SL MICE CLOSER MIMICS ALZHEIMER'S DISEASE SPATIO‐TEMPORAL PATHOLOGY
Author(s) -
Aguilo Meritxell,
Auer Ewald,
Dobrovich Balázs,
Neddens Joerg,
Flunkert Stefanie,
Zimmermann Robert,
Hutter-Paier Birgit
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.2018.06.1441
Subject(s) - tauopathy , entorhinal cortex , senile plaques , pathology , pathological , neocortex , neuroscience , tau pathology , tau protein , genetically modified mouse , neurofibrillary tangle , pathological staging , alzheimer's disease , disease , transgene , hippocampus , neurodegeneration , biology , medicine , biochemistry , gene
Background: Alzheimer’s disease (AD) brains are diagnosed under the concomitant expression of twomain pathological hallmarks: (2) Neurofibrillary tangles (NFT) composed of hyperphosphorylated Tau aggregates, and (2) senile plaques comprising insoluble b-amyloid (Ab). Mentioned pathological events do not develop in the same brain region; while NFTs production starts in the entorhinal and transentorhinal cortex, Ab plaque aggregation begins in the neocortex. Moreover, the onset of both pathologies is not triggered at the same time. Unfortunately, the current use of inappropriate animal models is leading to a misinterpretation of results and thus delaying the discovery of a cure for this disease. Therefore, a rodent model reproducing the APP and Tau pathology in a spatio-temporal way is mandatory in order to better understand the underlying mechanisms of AD and to obtain valid results in AD preclinical trials. Methods: To generate such a model, we virally induced the expression of pathological human Tau in the entorhinal cortex (ERC) of APPSL transgenic mice by stereotactic injection. Results: After assessment of stable exogenous Tau expression, histological analysis revealed distinctive phosphorylation patterns of Tau including NFT biomarkers in AD-related regions depending on protein residue, brain region and the presence or absence of Ab pathology. Such patterns were always compared to human AD patient’s brain tissue. Interestingly, pathological Tau spreading could be detected in ERC-connected areas, as described by Braak and Braak, 1991. On the other hand, plaque load was also exacerbated when tauopathy was induced, thus, indicating synergistic AbTau effects. Besides, biochemical CSF and plasma analyses point to altered Ab and Tau ratios. Furthermore, impairments on spatial navigation and memory were detected in these animals. Conclusions: We reproduced Ab and Tau pathologies closer mimicking the spatio-temporal patterns typically found in AD patients. Likewise, synergistic Ab-Tau effects also emerged under these conditions, mechanism of very high pursuit for AD researchers. This model might therefore be valuable to reliably test new compounds against AD.