P1‐142: Using DTI for noninvasive evaluation of axonal damage caused by exposure of axon terminals to beta‐amyloid

Abstract

Background: Amyloid Beta (Ab) is the major toxic mediator responsible for synaptic deficits in the early stage of Alzheimer's disease (AD). Recent studies showed that synaptic Ab can further cause distal axonopathy and neurodegeneration leading to neuronal loss. We explored an in vivo setup to demonstrate the synaptic Ab to cause pre-synaptic axonal degeneration. Methods: Ab1-42 (4 n mole, N = 6) or saline (N = 6) were injected at the right optic tract axonal terminals in 12-week-old C57BL/6 mice. In 1 and 3 months after Ab injection, mice were placed in a Bruker 4.7T small animal MRI for Diffusion Tensor Imaging (DTI) with slice thickness 0.5 mm, field of view of 2cm x 2cm and matrix 128 x 128 (zero filling to 256 x 256) to cover the visual system from eyes to superior colliculus. Animals were then sacrificed. The optic tract and nerve were examined using a primary antibody against phosphorylated neurofilament (pNF, SMI-31) and myelin basic protein (MBP). Results: In optic tract, the Ab-injected side (right side) of the tracts showed a 12-16% decrease of axial diffusivity (P<0.05) in 1-3 months. As for optic nerves, DTI did not change until 3 months with a significant 13% reduction of Tr (P<0.05) in the left nerves. Immunohistochemistry showed a 30% loss of SMI-31 axonal counts in the right optic tract suggesting axonal damage. Conclusions: This is the first study demonstrated distal axonal damage in vivo induced by an exposure of axonal terminal to Ab. We used the unique anatomical feature of retinal ganglion cells with their cell bodies in the eye but the elongated axons reaching to the middle of the brain. Injecting Ab in the axonal terminals caused optic tract axonal damage in 1-3 months detected by DTI, confirmed by immunohistochemistry. This finding has significant clinical impact as to use DTI for diagnosis of AD and evaluation of the treatment.