Monoamine‐activated α 2 ‐macroglobulin inhibits choline acetyltransferase of embryonic basal forebrain neurons and reversal of the inhibition by NGF and BDNF but not NT‐3

Monoamine‐activated α 2 ‐macroglobulin (α 2 M) 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 α 2 M. The objectives of this study are to determine whether monoamine‐activated α 2 M 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 α 2 M (MA‐α 2 M) and serotonin‐activated α 2 M (5HT‐α 2 M) can dose‐dependently suppress the expression of normal basal levels of ChAT activity in embryonic rat basal forebrain cells in vitro, while normal α 2 M has little or no effect. As little as 0.35 μM monoamine‐activated α 2 M 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 α 2 M‐suppressed cells can increase ChAT activity back to its normal levels, while NT‐3 can not. These results demonstrate that (1) monoamine‐activated α 2 M 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 α 2 M inhibition. The potential physiological role of monoamine‐activated α 2 M and neurotrophins in the degeneration and regeneration of cholinergic neurons is discussed. In addition, we propose that α 2 M may serve as an important tool for evaluating the roles of growth factors in the nervous system. © 1994 Wiley‐Liss, Inc.