ISDN2012_0264: New approaches to disease modifying therapies for Alzheimer's disease

ular code has not been elucidated. We found that in mouse embryos the transcription factor POU3F1/SCIP is selectively expressed in motor neurons innervating distant muscle targets (diaphragm, distal forelimb and distal hindlimb) but not in pools innervating more proximal muscles. In pou3f1 null embryos, whereas all proximal muscles were normal, none of the targets of the POU3F1-expressing motor neurons ever became fully innervated, and motor neurons whose axons failed to reach their target subsequently died. POU3F1 therefore triggers a program for innervation of distant muscle targets that is common to motor pools at multiple rostrocaudal levels. To define the signaling pathways underlying axonal growth, we screened a 50,000-compound library using an in vitro assay in which mouse or human ES cell-derived motor neurons are grown on inhibitory substrata. The most potent hits were the cholesterollowering drugs statins. When applied to human ES cell-derived motor neurons they induce a 5-fold increase in axon growth over the first 20 h. In vivo, they enhance optic nerve regeneration 5-fold over controls. Statins stimulate motor axon growth by inhibiting HMG-CoA reductase and thereby downstream protein prenylation. Since HMG-CoA reductase is expressed in motor neurons at high levels, it may potentially play a role in inhibiting axonal growth in multiple contexts. Overall, these studies show that a combination of transcriptional and post-translational mechanisms govern motor axon length and suggest that they may be potential therapeutic targets in situations requiring stimulation of axonal growth. We are grateful to the following for supporting this work: NINDS, P2ALS, Project A.L.S., New York State Spinal Cord Injury Board, NYSTEM.