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The effect of Amyloid Precursor Protein (APP) and APP-cleavage Products on Spinal Locomotive Circuit

  • Author(s): Huang, Ruyi
  • Advisor(s): Lu, Daniel C
  • Edgerton, Victor R
  • et al.
Abstract

Amyloid Precursor Protein (APP) was first identified in 1987 as one of the most important biomarkers in the Alzheimer’s disease (AD) subject brain tissue. Besides being involved in AD cognitive deficits, there is an accumulating body of evidence supports that APP and APP-cleavage products participate in multiple pathological and physiological processes in brain, spinal cord and the peripheral nervous system. In this study, we are interested in the effect of APP and APP-cleavage products on spinal circuit based locomotion. While the cognitive deficits related to AD have being thoroughly studied, locomotion impairments observed in AD patients as well as in transgenic model animals are understudied. Locomotion deficits like loss of balance and slowness in stepping speed were previously thought to be caused by brain degeneration and only occurring late in the disease progression (3). However, there is evidence showing that motor deficits precede cognitive failure (4). Recent researches show that, spinal cord changes have been observed in early stage of AD. It is possible that AD pathology also happens locally in the spinal cord, contributing to AD-related motor deficits.

In this study, I aim to address two hypotheses:

1) APP and APP-cleavage products in spinal cord participate in locomotion regulation in an expression dependent manner;

2) APP and its cleavage products impair neuronal plasticity in spinal cord as they do in the brain.

To test these two questions, I investigated the locomotion and the spinal cord changes in human mutated amyloid precursor protein (hAPP) over-expressing model mice, PDGFβ-APPSw/Ind (J20). The locomotion of J20 mice was tested before and after complete spinal cord transection, and the spinal learning was also evaluated by an instrumental learning paradigm, paw withdrawal learning paradigm (PaWL). Changes in locomotion kinematics patterns and spinal learning have been detected in J20 mice when compared to their WT littermates. These alternations are correlated to the lumbar spinal hAβ expression level and down-regulating the spinal Aβ expression levels can restore locomotion function in both intact and spinal cord transected J20 mice.

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