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P1‐043: Low level of nuclear phosphorylated tau is associated with cognitive impairment at early stage of the disease whereas an increase in the amount of this protein associates with neuronal death
Author(s) -
Di Jing,
Alonso Alejandra,
Elidrissi Abdeslem
Publication year - 2015
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.2015.06.239
Subject(s) - genetically modified mouse , tauopathy , tau protein , transgene , immunostaining , neurodegeneration , phosphorylation , astrocytosis , forebrain , biology , microbiology and biotechnology , morris water navigation task , chemistry , neuroscience , hippocampus , alzheimer's disease , biochemistry , immunohistochemistry , medicine , central nervous system , immunology , gene , disease
Background:A huge literature has grabed the widely attention that aberrant tau hyperphosphorylation is central to Alzheimer’s disease and related dementias. Unfortunately, our understanding of the functional effects of combintorial tau phosphorylation remains extremely limited, as well as the precise molecular mechanisms by which tau mediates neuronal death remain elusive. Methods:A new mouse model expressing an inducible human pseudophosphorylated tau at positions 199, 212, 231 and 262, as well as R406W mutation (Pathological Human Tau, PH-Tau) was created. A responder transgene mouse line consisting of a tetracycline operon–responsive element (TRE) placed upstream of a cDNA encoding PH-Tau was generated; then crossed with a tet-off B6Tg(Camk2a-tTA) mouse (ordered from Jackson lab). These double transgenic mice expressing a constitutively active PH-Tau gene were grouped as low levels of PH-Tau (suppressed by Doxycycline) mice (n1⁄430), and high levels of PH-Tau(induced by taking off Doxcycline) mice (n1⁄430). Non-transgenic micewere age-matched controls (n1⁄430). PH-Tau expression levels and localization were determined by immunostaining and western blots; neuronal loss and astrocytosis were analyzed by immunostaining; Morris Water Maze, Novel objective recogition, and Passive avoidance were used to assess the behavioral impairments. Results: The CaMKIIa promoter directs the transgene expression to the forebrain, when this model expresses low levels of PH-Tau, it appears mainly oligomer tau (w100KD); upon induction, the PH-Tau is mostly truncated at D421 (w46KD) and aggregated, and both species PHTau induce endogenous tau aggregation. Most importantly, PHTau induces neuronal loss, synaptic dysfunction, astrocytosis, and early behavioral impairments even with low levels of expression and without the presence of NFTs. Conclusions: In this model of tauopathy, phosphorylated Tau is sufficient to cause cognitive decline and neuronal loss through the two toxic tau species. This mouse seems to recapitulate early molecular events in Alzheimer’s disease and could serve as an in vivo model to develop early diagnostics and/or novel therapeutics.