Soluble Amyloid-β in the Lumbar Spinal Cord Impairs Locomotion and Motor Plasticity in J20 Mice

Patients with Alzheimer’s disease (AD) and mild dementia often present with motor deficits prior to observable cognitive decline. These deficits include slowed stepping and imbalanced gait. Our previous studies proposed amyloid-β and its precursor, amyloid precursor protein (APP), as having a role in AD-related gait disturbances by studying quadrupedal locomotion in APP-overexpressing transgenic J20 mice. However, the effect of Aβ/APP on spinal cord plasticity and recovery from injury has yet to be studied. We hypothesized that the presence of Aβ/APP in J20 mice will significantly impair recovery of locomotor function following spinal cord injury. Spinal cord injury was induced in wild type (WT) and J20 AD mice via complete transection of the spinal cord at the T10 level. To further evaluate whether the effect of Aβ/APP on plasticity was causative, we gave a gamma secretase-inhibitor (GSI) treatment, an Aβ inhibitor, to half of the mice at random. Mice were grouped by age, into 3-4 month and 10-13 month groups. Mice were fixed to a treadmill to assess their ability to produce hindlimb locomotion in congruence with the treadmill in a bipedal stepping task. To monitor long-term plasticity, hindlimb motor output data for both groups was collected at baseline and every week for 8 weeks post injury. Motion capture data was processed via SIMI, allowing for semi-automatic motion tracking and quantification of motion features. Extracted features included step length and height, average velocity, angle of movement, and angular velocity. Following the 8-week recovery period, both groups of mice showed improved motor control, which was signified by alternating step count during the recording period. There was a significant decrease of the alternating step count in 10-13mon J20 mice compared to their WT littermates (p=0.0259), but there was no significant difference in 3-4mon mice (p=0.4223). The J20 AD mice showed significantly less recovery at all time points throughout the recovery period. In the mice that received the GSI treatment, there was no significant difference between 10mon J20 and their WT littermates (p= 0.9804) or 3-4mon J20 mice and their WT littermates (p> 0.9999). We concluded that the spontaneous recovery of locomotion following complete thoracic transection was blocked in J20 AD mice as compared to WT, while introducing GSI to inhibit Aβ recovered locomotion in the affected mice. Our conclusions suggest that the presence of Aβ and APP can drastically effect plasticity even in the spinal cord, further exemplifying the role of these proteins in contributing to AD-related motor deficits.

NIH National Institute of Biomedical Imaging and Bioengineering (NIBIB), U01EB015521-05; NIH, National Institute on Drug Abuse (NIDA), R01DA047637-01A1

This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.