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

• Published in: NeuroImage (Orlando, Fla.) Vol. 189; pp. 180 - 191
• Main Authors: Nishioka, Christopher, Liang, Hsiao-Fang, Barsamian, Barsam, Sun, Shu-Wei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2019; Elsevier Limited
• Subjects: Alzheimer's disease; Amyloid beta; Amyloid beta-Peptides - administration & dosage; Amyloid beta-Peptides - pharmacology; Animal cognition; Animals; Anisotropy; Axons; Brain research; Cognitive ability; Diffusion Tensor Imaging; Disease Models, Animal; Drug dosages; EpoD; Epothilones - administration & dosage; Epothilones - pharmacology; Geniculate Bodies - drug effects; Histology; Injection; Laboratory animals; Lateral geniculate nucleus; Magnetic resonance imaging; Medical imaging; Mice; Multimedia; Nerve Degeneration - chemically induced; Nerve Degeneration - diagnostic imaging; Nerve Degeneration - drug therapy; Nerve Degeneration - prevention & control; Neural networks; Neurodegeneration; Neurodegenerative diseases; Optic nerve; Optic tract; p301L tau; Pathology; Patients; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Peptides; Phosphorylation; Retina; Retinal ganglion cell; Retinal ganglion cells; Retinal Ganglion Cells - drug effects; Retrograde degeneration; Substantia alba; Synapses; Tau protein; Tauopathies - chemically induced; Tauopathies - diagnostic imaging; Tauopathies - drug therapy; Tauopathies - pathology; Transgenic mice; Tubulin Modulators - administration & dosage; Tubulin Modulators - pharmacology; Visual system; White Matter - diagnostic imaging; White Matter - drug effects; Retrograde degeneration; EpoD; Amyloid beta; p301L tau; Diffusion tensor imaging; Retinal ganglion cell
• ISSN: 1053-8119; 1095-9572; 1095-9572
• DOI: 10.1016/j.neuroimage.2019.01.007

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. However, how DTI changes related to the development of Amyloid beta (Aβ) and tau pathology, two key hallmarks of AD, remain elusive. We hypothesized that tauopathy induced by Aβ could initiate an axonal degeneration, 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. Longitudinal DTI was conducted to detect changes in the optic tract (OT) and optic nerve (ON), containing the distal and proximal segments of RGC axons, respectively. Our results showed DTI changes in OT (significant 13.2% reduction in axial diffusion, AxD vs. vehicle controls) followed by 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 prevent the axon loss in AD. •Aβ injection into the Lateral Geniculate Nucleus of p301L mice precipitated degeneration of Retinal Ganglion Cells.•Degeneration induced by Aβ was detectable by Diffusion Tensor Imaging early in OT and later in ON, confirmed by histology.•Treating mice with microtubule stabilizer EpoD ameliorated Aβ-induced tauopathy, axonal damage, and neuronal loss.