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.