Monoamine-activated α2-macroglobulin inhibits choline acetyltransferase of embryonic basal forebrain neurons and reversal of the inhibition by NGF and BDNF but not NT-3

Monoamine-activated α₂-macroglobulin (α₂M) has recently been shown to inhibit the growth and survival of cholinergic neurons of the basal forebrain (Liebl and Koo: J Neurosci Res 35:170–182, 1993). The mechanism of this inhibitory effect is believed to involve the regulation of growth factor activities by α₂M. The objectives of this study are to determine whether monoamine-activated α₂M can inhibit choline acetyltransferase (ChAT) activity of cholinergic basal forebrain neurons, and whether some common neurotrophins in the CNS can reverse the inhibition. This study demonstrates that both methylamine-activated α₂M (MA-α₂M) and serotonin-activated α₂M (5HT-α₂M) can dose-dependently suppress the expression of normal basal levels of ChAT activity in embryonic rat basal forebrain cells in vitro, while normal α₂M has little or no effect. As little as 0.35 μM monoamine-activated α₂M can suppress the ChAT activity, whereas either nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF), but not neurotrophin-3 (NT-3), stimulates ChAT expression of these cells. The addition of either NGF or BDNF to the α₂M-suppressed cells can increase ChAT activity back to its normal levels, while NT-3 can not. These results demonstrate that (1) monoamine-activated α₂M is a potent non-cytotoxic inhibitor of the ChAT activity in cholinergic basal forebrain neurons, and (2) NGF and BDNF are capable of not only stimulating the ChAT activity but can also specifically reverse the α₂M inhibition. The potential physiological role of monoamine-activated α₂M and neurotrophins in the degeneration and regeneration of cholinergic neurons is discussed. In addition, we propose that α₂M may serve as an important tool for evaluating the roles of growth factors in the nervous system. © 1994 Wiley-Liss, Inc.