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 2M) 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 alpha 2M. The objectives of this study are to determine whether monoamine-activated alpha 2M 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 alpha 2M (MA-alpha 2M) and serotonin-activated alpha 2M (5HT-alpha 2M) can dose-dependently suppress the expression of normal basal levels of ChAT activity in embryonic rat basal forebrain cells in vitro, while normal alpha 2M has little or no effect. As little as 0.35 microM monoamine-activated alpha 2M 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 alpha 2M-suppressed cells can increase ChAT activity back to its normal levels, while NT-3 can not. These results demonstrate that (1) monoamine-activated alpha 2M 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 alpha 2M inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Liebl
D J
DJ
Neuroscience Program, Northeastern Ohio Universities College of Medicine, Rootstown.
Koo
P H
PH
D000818:Animals; D015306:Biogenic Monoamines / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020933:Neurotrophin 3; D016548:Prosencephalon / Q000166:cytology*; D051381:Rats; D000511:alpha-Macroglobulins / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D015306:Biogenic Monoamines; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D000511:alpha-Macroglobulins; D002795:Choline O-Acetyltransferase