Alzheimer‘s disease (AD) is a neurodegenerative disorder characterized by Aβ deposition and neural networks disruption in the brain. We previously found that diosgenin, a constituent of Dioscorea Rhizoma, promoted long-distance axonal regeneration in the brains and recovered memory deficits in an AD model (5XFAD) mouse. In the present study, we aimed to clarify molecular mechanisms for accurate pathfinding of degenerated axons in AD brains.
Axon-regenerated neurons (after diosgenin administration) in the neural circuits contributing memory formation; from the hippocampus to the prefrontal cortex, were visualized by retrograde tracings. Naïve neurons and axon-regenerated neurons in the brain slices were individually captured by laser microdissection, and Galectin-1 was identified as a drastically upregulated molecule in axon-regenerated neurons by DNA microarray. Overexpression of Gelectin-1 in hippocampal neurons promoted axonal regeneration and recovered memory deficits in 5XFAD mice. Galectin-1 expressed on the membranes of growth cones and was attracted by extracellular Secernin-1 to promote axonal guidance from the hippocampus to the prefrontal cortex.
Our study identified a novel axonal guidance pair, Galectin-1 and Secernin-1, for axonal regeneration in AD brains, which is a promising novel therapeutic strategy for AD.