Gender effect on the accumulation of hyperphosphorylated tau in the brain of locus-ceruleus-injured APP-transgenic mouse

Locus ceruleus (LC) neurons are preferentially and initially affected in Alzheimer disease (AD); however, the impact of the loss of LC neurons on the pathological sequence of AD, including amyloid β-protein (Aβ) deposition and neurofibrillary tangle formation, has not been elucidated. In this study, we chemically injured LC neurons of the brains of familial AD-related amyloid precursor protein (APP)-transgenic mice using the LC-noradrenergic neuron-selective neurotoxin, N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP4). The levels of noradrenaline significantly decreased in the cerebral cortices of DSP4-treated mice. The deposition of amyloid fibrils was biochemically observed in the APP-transgenic mouse brains; however, those levels were not significantly altered following DSP4 treatment. In contrast, the levels of accumulated hyperphosphorylated tau markedly increased in the cerebral cortices of DSP4-treated female but not male APP-transgenic mice. Our results suggest that innervation from LC neurons and testosterone secretion are potent and mutually independent suppressors of amyloid-related accumulation of hyperphosphorylated tau in the brain.