Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ deposition and disruption of neural networks in the brain. We previously found that diosgenin, a constituent of Dioscorea Rhizoma, restored Aβ-induced axonal atrophy in neurons (in vitro) and recovered memory deficits in a mouse model of AD, 5XFAD. Importantly, we were the first to discover that diosgenin administration promoted long-distance axonal regeneration in 5XFAD mice brains. In the present study, we aimed to clarify molecular mechanisms for controlling accurate pathfinding of injured 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 selectively visualized by retrograde tracings. Naïve neurons and axon-regenerated neurons in the brain slices were separately captured by laser microdissection to serve DNA microarray. Overexpression of the gene, whose expression level was drastically elevated in axon-regenerated neurons, to the hippocampal neurons promoted axonal regeneration in the brain and recovered memory deficits in 5XFAD mice.
Our study identified key molecules for promoting axonal regeneration toward long distance away target area in AD brains. This finding proposes a novel therapeutic strategy for AD treatment.