The effects of apolipoprotein e deficiency on braincholinergic neurons

Abstract

Previous studies utilizing apolipoprotein E (apoE)-deficient mice revealed distinctdecreases in the levels of cholinergic synaptic markers of projecting basal forebrain cholinergicneurons and no such alterations in other brain cholinergic systems. In order to investigate themechanisms underlying these neuron-specific cholinergic effects, primary neuronal cultures fromapoE-deficient and control mice were prepared and characterized. These include basal forebraincultures, which are enriched in projecting cholinergic neurons, and cortical cultures, which containcholinergic interneurons. The levels of cholinergic nerve terminals in these cultures were assessedby ligand binding measurements of the levels of the vesicular acetylcholine transporter (VAChT).This revealed that basal forebrain cultures of apoE-deficient mice contain markedly lower VAChTlevels (∼50%) than do control cultures, but that VAChT levels of the corresponding corticalcultures of the apoE-deficient and control mice were the same. Time course studies revealed thatVAChT levels of the basal forebrain cultures increased with culture age, but that the relativereduction in VAChT levels of the apoE-deficient cholinergic neurons was unaltered and was thesame for freshly prepared and for 96 h old cultures. These in vitro observations are inaccordance with the in vivo findings and suggest that projecting basal forebraincholinergic neurons, but not cholinergic interneurons, are markedly dependent on apoE and thatsimilar mechanisms mediate the in vivo and in vitro effects of apoE deficiencyon cholinergic function.