MONOAMINE-ACTIVATED ALPHA(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 alpha(2)-macroglobulin (alpha(2)M) has recently be en 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 reg ulation of growth factor activities by alpha(2)M. The objectives of th is study are to determine whether monoamine-activated alpha(2)M can in hibit choline acetyltransferase (ChAT) activity of cholinergic basal f orebrain neurons, and whether some common neurotrophins in the CNS can reverse the inhibition. This study demonstrates that both methylamine -activated alpha(2)M (MA-alpha(2)M) and serotonin-activated alpha(2)M (5HT-alpha(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 alpha(2)M has little or no effect. As little as 0.35 mu M monoamine-activated alpha(2)M can suppress the ChAT activit y, whereas either nerve growth factor (NGF) or brain-derived neurotrop hic factor (BDNF), but not neurotrophin-3 (NT-3), stimulates ChAT expr ession of these cells. The addition of either NGF or BDNF to the alpha (2)M-suppressed cells can increase ChAT activity back to its normal le vels, while NT-3 can not. These results demonstrate that (1) monoamine -activated alpha(2)M is a potent non-cytotoxic inhibitor of the ChAT a ctivity in cholinergic basal forebrain neurons, and (2) NGF and BDNF a re capable of not only stimulating the ChAT activity but can also spec ifically reverse the alpha(2)M inhibition. The potential physiological role of monoamine-activated alpha(2)M and neurotrophins in the degene ration and regeneration of cholinergic neurons is discussed. In additi on, we propose that alpha(2)M may serve as an important tool for evalu ating the roles of growth factors in the nervous system. (C) 1994 Wile y-Liss, Inc.