Axon degeneration is key component of neuronal death in amyloid-β toxicity

Depending upon the stimulus, neuronal cell death can either be triggered from the cell body (soma) or the axon. We investigated the origin of the degeneration signal in amyloid beta (A beta) induced neuronal cell death in cultured in vitro hippocampal neurons. We discovered that A beta(1-42) toxicity-induced axon degeneration precedes cell death in hippocampal neurons. Overexpression of Bcl-xl inhibited both axonal and cell body degeneration in the A beta-42 treated neurons. Nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) blocks axon degeneration in a variety of paradigms, but it cannot block neuronal cell body death. Therefore, if the neuronal death signals in A beta(1-42) toxicity originate from degenerating axons, we should be able to block neuronal death by inhibiting axon degeneration. To explore this possibility we over-expressed Nmnat1 in hippocampal neurons. We found that inhibition of axon degeneration in A beta(1-42) treated neurons prevented neuronal cell death. Thus, we conclude that axon degeneration is the key component of A beta(1-42) induced neuronal degeneration, and therapies targeting axonal protection can be important in finding a treatment for Alzheimer's disease. (C) 2013 Elsevier Ltd. All rights reserved.