Intracellular mechanisms of amyloid β-peptide Aβ25-35 induced neurite outgrowth inhibition in vitro

A previous study of the effects of freshly-solubilized synthetic amyloid P-peptides (AP) on the outgrowth of neurites from high density peripheral and central nervous system neuronal cultures in vitro has shown that A beta(25-35), but neither A beta(1-40) nor A beta(1-28), inhibits outgrowth In a concentration dependent and reversible manner. This A beta(25-35)-induced inhibition of neurite growth may be relevant to disconnectionist models of Alzheimer's disease pathogenesis, since N-terminally truncated amyloid P-peptides are found in the diffuse plaques observed early in the disease. The cellular mechanisms underlying this activity of A beta(25-35) were sought by using various pharmacological agents, reported to affect other aspects of A beta neurotoxicity, in a neurite outgrowth assay in combination with A beta(25-35). A beta(25-35)-induced neurite growth inhibition was partially abrogated by co-administration of the L-type calcium channel antagonist nifedipine and by the antioxidant n-propyl gallate, but dantrolene sodium and Substance P were without effect at concentrations previously reported to block other aspects of A beta neurotoxicity in vitro. This suggests that influx of extracellular Ca2+ and changes in intracellular oxidation state contribute to A beta(25-35)-induced neurite growth inhibition, but destabilization of intracellular Ca2+ stores and tachykinin receptor antagonism do not. These findings may have pathogenetic and therapeutic implications for Alzheimer's disease.