Axonopathy Likely Initiates Neuropathological Processes Via a Mechanism of Axonal Leakage in Alzheimer's Mouse Models

Background: The formation of hyperphosphorylated tau and the production of β-amyloid are thought to be critical steps contributing to the pathological mechanisms in Alzheimer’s disease (AD). However, there has been a long-lasting debate over their importance in the onset of AD. Recent studies have demonstrated that axonopathy is considered as an early neuropathological change of AD. However, the exact relationship between the development of axonopathy and the classic neuropathological changes such as senile plaques (SPs) and neurofibrillary tangles (NFTs) is unclear. Objective: The aim of this study was to investigate whether the formation of SPs and NFTs is associated with the development of axonal leakage. Method and Results: Here we show that the formation and development of axonal leakage - a novel axonopathy is an age-dependent process, accompanied by swellings of axons and varicosities and associated with chronic oxidative stress induced by thiamine deficient (TD) diet in Kunming mice. In an APP/PS1 transgenic mouse model of AD, axonal leakage appears at 3 months, becomes more obvious at 6 months and severe, beyond 1 year. We also show that slight axonal leakage is related to the formation of hyperphosphorylated tau, but not plaques, and that only severe axonal leakage accompanied by the extensive swollen axons and varicosities, and overproduction of β-amyloid leads to the formation of SPs and hyperphosphorylated tau. Conclusion: These data provide an explanation of the common origin and development of SPs and NFTs, and suggest that axonal leakage might be a key event in the development of the neuropathological processes in AD.