Characterization of a Novel Mouse Model of Alzheimer's Disease--Amyloid Pathology and Unique ?-Amyloid Oligomer Profile.

ABSTRACT: Amyloid plaques composed of ?-amyloid (A?) protein are a pathological hallmark of Alzheimer's disease. We here report the generation and characterization of a novel transgenic mouse model of A? toxicity. The rTg9191 mice harbor a transgene encoding the 695 amino-acid isoform of human amyloid precursor protein (APP) with the Swedish and London mutations (APPNLI) linked to familial Alzheimer's disease, under the control of a tetracycline-response element, as well as a transgene encoding the tetracycline transactivator, under the control of the promoter for calcium-calmodulin kinase II?. In these mice, APPNLI is expressed at a level four-fold that of endogenous mouse APP and its expression is restricted to forebrain regions. Transgene expression was suppressed by 87% after two months of doxycycline administration. Histologically, we showed that (1) A? plaques emerged in cerebral cortex and hippocampus as early as 8 and 10.5-12.5 months of age, respectively; (2) plaque deposition progressed in an age-dependent manner, occupying up to 19% of cortex at ~25 months of age; and (3) neuropathology--such as abnormal neuronal architecture, tau hyperphosphorylation and misfolding, and neuroinflammation--was observed in the vicinity of neuritic plaques. Biochemically, we determined total A? production at varied ages of mice, and we showed that mice produced primarily fibrillar A? assemblies recognized by conformation-selective OC antibodies, but few non-fibrillar oligomers (e.g., A?*56) detectable by A11 antibodies. Finally, we showed that expression of the tetracycline transactivator resulted in reduced brain weight and smaller dentate-gyrus size. Collectively, these data indicate that rTg9191 mice may serve as a model for studying the neurological effects of the fibrillar A? assemblies in situ.

SUBMITTER: Liu P 

PROVIDER: S-EPMC4422728 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature