Mechanism of accumulation of amyloid and neurofibrillary tangles in Alzheimer's disease brain

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To clarify the mechanism of accumulation of amyloid β protein (Aβ) and neurofibrillary tangles (NFT) in brains of Alzheimer's disease (AD), we first examined APPsw mice expressing human βAPP695ΔNL demonstrating substantial Aβ amyloidosis and spatial memory deficit (K Hsiao et al. Science 1996). We found cored, diffuse plaques and amyloid angiopathy composed of various Aβ species with N- and C-terminal modifications in the brain of APPsw mice. The cored plaques substituted normal brain tissues with focal loss of neurons and synapses, and caused subsequent pathology such as dystrophic neurites and appearance of hyperphosphorylated tau. However, neither NFT nor neuronal cell death was observedNext, we have generated transgenic mice (Tg) overexpressing the R406W mutant form of human 4-repeat longest tau associated with fronto-temporal dementia with parkinsonism linked to chromosome 17. These mice developed widespread tau accumulation in cytoplasma and neurites of neuronal cells in fronto-t … More emporal cortex, hippocampus and amygdaloid body accompanied by gliosis. Accumulated tau was highly phosphorylated, and composed of straight tubules by electron microscopy. Glycogen synthase kinase 3 β and cyclin-dependent kinase 5 were closely involved in phosphorylation and accumulation of tau. Western blot analysis demonstrated sarkosyl insoluble tau deposited in brains. They showed motor disturbance and memory loss. These findings demonstrate that our Tau R406W mice will provide a useful model for testing future therapeutic agents and understanding the pathogenesis of secondary tauopathies induced by Aβ accumulation in AD.Finally, we crossed Tau R406W mice with APPsw mice. The pathology of Aβ amyloidosis was similar in both double Tg and APPsw mice. Gallyas silver-staining showed enhanced tau pathology in the hippocampus of double Tg relative to Tau R406W mice. These findings suggest that Aα amyloidosis causes subsequent pathology such as accumulation of phosphorylated tau, neuronal loss and memory disturbance, and that it is most important to treat Aα amyloidosis for cure of AD. Less