FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington's disease

K Jin, M LaFevre-Bernt, Y Sun… - Proceedings of the …, 2005 - National Acad Sciences
K Jin, M LaFevre-Bernt, Y Sun, S Chen, J Gafni, D Crippen, A Logvinova, CA Ross…
Proceedings of the National Academy of Sciences, 2005National Acad Sciences
There is no satisfactory treatment for Huntington's disease (HD), a hereditary
neurodegenerative disorder that produces chorea, dementia, and death. One potential
treatment strategy involves the replacement of dead neurons by stimulating the proliferation
of endogenous neuronal precursors (neurogenesis) and their migration into damaged
regions of the brain. Because growth factors are neuroprotective in some settings and can
also stimulate neurogenesis, we treated HD transgenic R6/2 mice from 8 weeks of age until …
There is no satisfactory treatment for Huntington's disease (HD), a hereditary neurodegenerative disorder that produces chorea, dementia, and death. One potential treatment strategy involves the replacement of dead neurons by stimulating the proliferation of endogenous neuronal precursors (neurogenesis) and their migration into damaged regions of the brain. Because growth factors are neuroprotective in some settings and can also stimulate neurogenesis, we treated HD transgenic R6/2 mice from 8 weeks of age until death by s.c. administration of FGF-2. FGF-2 increased the number of proliferating cells in the subventricular zone by ≈30% in wild-type mice, and by ≈150% in HD transgenic R6/2 mice. FGF-2 also induced the recruitment of new neurons from the subventricular zone into the neostriatum and cerebral cortex of HD transgenic R6/2 mice. In the striatum, these neurons were DARPP-32-expressing medium spiny neurons, consistent with the phenotype of neurons lost in HD. FGF-2 was neuroprotective as well, because it blocked cell death induced by mutant expanded Htt in primary striatal cultures. FGF-2 also reduced polyglutamine aggregates, improved motor performance, and extended lifespan by ≈20%. We conclude that FGF-2 improves neurological deficits and longevity in a transgenic mouse model of HD, and that its neuroprotective and neuroproliferative effects may contribute to this improvement.
National Acad Sciences