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[P4–048]: CONCOMITANT EXPRESSION OF INDUCED AAV‐P301L TAU AND TRANSGENIC β‐AMYLOID IN A MOUSE MODEL MIMICKING HUMAN ALZHEIMER's DISEASE
Author(s) -
Aguilo Meritxell,
Dobrovich Balázs,
Neddens Joerg,
Flunkert Stefanie,
Taub Nicole,
Zimmermann Robert,
HutterPaier Birgit
Publication year - 2017
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.2017.06.1912
Subject(s) - entorhinal cortex , senile plaques , tauopathy , neocortex , genetically modified mouse , neuroscience , tau protein , transgene , amyloid (mycology) , hippocampus , biology , pathological , cortex (anatomy) , pathology , disease , alzheimer's disease , medicine , neurodegeneration , biochemistry , gene
Background:Alzheimer’s disease (AD) is an irreversible neurodegenerative process in whichmemory functions, intellectual abilities and reasoning skills are progressively lost. AD brains are diagnosed under the co-existence of two main pathological hallmarks: (1) Neurofibrillary tangles (NFT) composed of hyperphosphorylated Tau aggregates, and (2) senile plaques comprising of insoluble bamyloid (Ab). Mentioned pathological events do not develop in the same brain region; while NFT production starts in the entorhinal and transentorhinal cortex, Ab plaque loading begins in the neocortex. Moreover, the onset of both pathologies is not triggered at the same time. Therefore, a mouse model reproducing both spatio-temporal conditions is mandatory in order to obtain trustworthy results in AD preclinical trials. Methods: To generate such a model, we virally induced the expression of P301L human Tau, which is the most prevailing mutation in various types of 4R tauopathies, in the entorhinal cortex of the APPSL transgenic mouse by stereotactic injection. Results: Biochemical and histological analysis revealed stable expression of P301LTau in entorhinal cortex and connected brain areas for at least 9 months after injection. Furthermore, besides the high density of senile plaques, several epitopes of aberrant and hyperphosphorylated Tau were characterized in AD-related regions including NFT biomarkers. Ongoing experiments aim to investigate the occurrence of synergistic effects between Ab and Tau in addition to the behavioral characterization of these mice. Conclusions: To summarize, we show that our inducible mouse model is a promising new tool which mimics spatio-temporal patterns of AD-related pathology. This model might be valuable to reliably test new compounds, and may potentially help decreasing clinical trial failures.