Diosgenin restores memory function via SPARC-driven axonal growth from the hippocampus to the PFC in Alzheimer’s disease model mice
Central nervous system axons have minimal capacity to regenerate in adult brains, hindering memory recovery in Alzheimer’s disease (AD). Although recent studies have shown that damaged axons sprouted in adult and AD mouse brains, long-distance axonal re-innervation to their targets has not been achieved. We selectively visualized axon-growing neurons in the neural circuit for memory formation, from the hippocampus to the prefrontal cortex, and showed that damaged axons successfully extended to their native projecting area in mouse models of AD (5XFAD) by administration of an axonal regenerative agent, diosgenin. In vivo transcriptome analysis detected the expression profile of axon-growing neurons directly isolated from the hippocampus of 5XFAD mice. Secreted protein acidic and rich in cysteine (SPARC) was the most expressed gene in axon-growing neurons. Neuron-specific overexpression of SPARC via AAV9 vector delivery in the hippocampus recovered memory deficits and axonal projection to the prefrontal cortex in 5XFAD mice. DREADDs (Designer receptors exclusively activated by designer drugs) analyses revealed that SPARC overexpression-induced axonal growth in the 5XFAD mouse brain directly contributes to memory recovery. Elevated levels of SPARC on axonal membranes interact with extracellular rail-like collagen type I to promote axonal remodeling along their original tracings in primary cultured hippocampal neurons. These findings suggest that SPARC-driven axonal growth in the brain may be a promising therapeutic strategy for AD and other neurodegenerative diseases.
This is the first study to show that axons in AD model mice extend toward a distant target region, in the accurate projecting area, which contributes to memory recovery. Diosgenin is a potential treatment agent to stimulate axonal growth via these mechanisms. Our findings suggest that axons in the brain have the capacity to growth, and that promoting axonal growth potentially comprises a promising therapeutic strategy for AD.
Original article information
Diosgenin restores memory function via SPARC-driven axonal growth from the hippocampus to the PFC in Alzheimer’s disease model mice.
Ximeng Yang, Chihiro Tohda