Study of Alzheimer's disease using transgenic mice: The mechanism of formation of brain Aβ amyloid and neurofibrillary tangles

Abstract

Background: The purpose of the present paper was to clarify the role of brain amyloid β protein (Aβ) in Alzheimer's disease (AD) with the eventual aim of developing new treatments.Methods: Three kinds of transgenic mice (Tg) were examined: those overexpressing βAPP695ΔNL (APPsw mice), those expressing the R406W mutant form of human 4‐repeat tau (tauR406W mice), and those with both βAPP695ΔNL and R406W mutant tau (APPsw × tau R406 double Tg).Results: First, cored plaques, diffuse plaques and amyloid angiopathy were detected in the brains of APPsw mice. Loss of neurons and synapses was seen in the cored plaques, and accumulation of phosphorylated‐tau in dystrophic neurites around the cored plaques. However, Neurofibrillary tangles were not seen. These mice displayed memory impairment and decreased levels of acetylcholine in the cortex and hippocampus. Second, tau R406W mice were produced. These mice developed motor disturbances and memory impairment, accompanied by gliosis and marked tau accumulation in neurons of the frontotemporal cortex, hippocampus and amygdala. No Aβ was detected. Third, APPsw × tauR406W double Tg were produced. The pattern of Aβ deposition was similar in these double Tg and the APPsw mice. Gallyas silver‐staining showed greater levels of tauopathy in the hippocampus in these double Tg compared to the tauR406W mice.Conclusion: These findings suggest that deposition of brain Aβ is the initial event leading to subsequent disease such as accumulation of phosphorylated tau, neuronal loss and memory disturbance, and that the treatment of brain Aβ should be the first priority in finding a cure for AD.