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• W2036526123 abstract "Three pathologies must be present in the brain for a definitive diagnosis of Alzheimer's disease (AD): amyloid plaques composed of β-amyloid aggregates, neurofibrillary tangles composed of hyperphosphorylated and aggregated tau, and neuron loss. The amyloid hypothesis proposes that β-amyloid accumulation is toxic to the brain resulting in hyperphosphorylation of tau, neuronal death and cognitive deficits. Replication of AD-like pathology in mice by the sole accumulation of amyloid peptides leading to abnormal tau pathology, neuronal loss and cognitive dysfunction has proven to be elusive. Incomplete pathological models that show abundant amyloid deposition with little or sparse tau pathology, rare neuronal loss and limited changes in learning and memory behaviors have been most commonly generated. We report here a method to progress an amyloid depositing APP transgenic mouse to a more complete Alzheimer's-like pathology with robust behavioral deficits. This is accomplished by genetically removing NOS2, and its iNOS protein product from mice that concomitantly express mutated human APP and deposit Aβ. Two mouse strains using different human APP mutations were crossed to a NOS2 knockout background. These bigenic APP/NOS2-/- mice closely replicate human disease and demonstrate native mouse tau pathology including hyperphosphorylated and aggregated tau redistributed to the somatodendritic regions of neurons. Extensive neuron loss (up to 40% in the CA3 region of the hippocampus) in the presence of amyloid deposition is observed in both bigenic models. NPY neurons that are known to be vulnerable in human AD are also particularly vulnerable in this mouse model and demonstrate up to 65% loss in the hippocampus. Using the radial arm water maze and Barnes maze, we also show that the neuron loss is associated with significant deficits in learning and memory. In addition, the profile of genes associated with inflammation in the APP/NOS2-/- mice are similar to the profiles observed in AD brain. These data support the amyloid cascade hypothesis of AD, but also suggest that NOS2 and its enzymatic product NO play a protective role in reducing downstream pathology. Furthermore, the data strongly implicate a unmistakable role for tau pathology in the neuronal loss and associated behavioral deficits." @default.
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• W2036526123 date "2008-07-01" @default.
• W2036526123 modified "2023-10-16" @default.
• W2036526123 title "P1-050: Progression to a full spectrum of Alzheimer's-like pathology in animal models of amyloid deposition by reduction in NOS2" @default.
• W2036526123 doi "https://doi.org/10.1016/j.jalz.2008.05.635" @default.
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