Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model

Publication date: Available online 7 January 2019

Source: NeuroImage

Author(s): Christopher Nishioka, Hsiao-Fang Liang, Barsam Barsamian, Shu-Wei Sun

Abstract

White matter abnormalities, revealed by Diffusion Tensor Imaging (DTI), are observed in patients with Alzheimer's Disease (AD), representing neural network deficits that underlie gradual cognitive decline in patients with AD. However, how DTI changes are related to the development of Amyloid beta (Aβ) and tau pathology, two key hallmarks of AD, remains elusive. We hypothesized that tauopathy induced by Aβ could initiate an axonal degeneration process, leading to DTI-detectable white matter abnormalities. We utilized the visual system of the transgenic p301L tau mice as a model system. Aβ was injected in Lateral Geniculate Nucleus (LGN), where the Retinal Ganglion Cell (RGC) axons terminate, and longitudinal DTI was conducted to detect changes in the optic tract (OT, containing the distal segment of RGC axons) and optic nerve (ON, containing the proximal segment of RGC axons). Our results showed early DTI changes in OT (significant 13.2% reduction in axial diffusion, AxD vs. vehicle controls) followed by later significant alterations in ON AxD and fractional anisotropy, FA. Histology data revealed loss of synapses, RGC axons and cell bodies resulting from the Aβ injection. We further tested whether microtubule-stabilizing compound Epothilone D (EpoD) could ameliorate the damage. EpoD co-treatment with Aβ was sufficient to prevent Aβ-induced axon and cell loss. Using an acute injection paradigm, our data suggest that EpoD may mediate its protective effect by blocking localized, acute Aβ-induced tau phosphorylation. This study demonstrates white matter disruption resulting from localized Aβ, the importance of tau pathology induction to changes in white matter connectivity, and the use of EpoD as a potential therapeutic avenue to block axon loss during disease.

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