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P1‐005: AAV‐based paradigm for amyloid and Tau pathology as in vivo model for Alzheimer's disease
Author(s) -
Jaworski Tomasz,
Dewachter Ilse,
Kügler Sebastian,
Leuven Fred
Publication year - 2008
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.2008.05.590
Subject(s) - neurodegeneration , extracellular , intracellular , genetically modified mouse , tauopathy , in vivo , hippocampus , amyloid precursor protein , tau protein , amyloid (mycology) , pathology , transgene , microbiology and biotechnology , neuroscience , alzheimer's disease , biology , chemistry , medicine , biochemistry , disease , gene
Background: Alzheimer’s disease (AD) is defined post-mortem by (i) extracellular amyloid plaques by accumulation of peptides derived from Amyloid Precursor Protein (APP) and by (ii) intracellular neurofibrillary tangles composed of hyper-phosphorylated protein tau. Accumulated amyloid peptides (A ) are proposed to trigger and/or aggravate tau pathology and thereby neurodegeneration. AD is always associated with inflammation, but relations between accumulation of pathogenic protein aggregates, inflammation and neurodegeneration remains unclear. Methods: Here we developed a novel in vivo model for AD pathology based on adenoassociated virus mediated expression of triple mutant APP (SwedishAustrian-London) and mutant Tau-P301L in mouse brain, either alone or in combination. Viruses were delivered stereotactically into the CA1 region of the hippocampus of non-transgenic mice. Results: Robust expression of APP and tau was evident in neurons of hippocampus and cortex as early as 3 weeks post-injection of either vector alone or combined. Besides accumulation of intra-cellular A , hyper-phosphorylation of tau was evident by reaction with Mabs AT8, AT180, AT270 among others. Occasional neurons contained tangle-like structures and intracellular A -aggregates both revealed histochemically (X34). At 3 months post-injection of APP-AAV, intracellular and diffuse extracellular amyloid deposits were evident, but no amyloid plaques yet. Remarkably, neuronal loss in CA1/2 was extensive in Tau-AAV injected mice but not in APP-AAV injected mice. Combined injection of APP-AAV and Tau-AAV increased the number of tangled neurons without apparent increasing neurodegeneration. The importance of this outcome, necessitates further analysis using different markers and quantification methods, which is ongoing. Conclusions: The novel paradigms provide independent and convincing evidence for the hypothesis that intra-neuronal accumulation of phosphorylated tau is the actual cause of neurodegeneration, not the formation of tangles nor the accumulation of aggregated amyloid peptides. Expression of mutant APP and mutant Tau was accompanied by inflammation, comprising microglial and astroglial activation, which appears due to the human proteins as it was not observed by intra-cerebral injection of EGFP-AAV. The important aspect of inflammation is therefore also accessible in this model, allowing study of all major aspects of AD pathology. P1-006 ACCUMULATION OF -AMYLOID PLAQUES WITH MICROGLIAL PHAGOCYTOSIS IN RABBITS FED WITH CHOLESTEROL-ENRICHED DIETS