Cholinergic systems and long-term potentiation in memory-impaired apolipoprotein E-deficient mice

Impairments in cholinergic neurotransmitter systems of the basal forebrain are a hallmark of Alzheimer's disease pathophysiology. The presence of the epsilon 4 allele of apolipoprotein E was recently implicated as a major ris k factor in both familial and sporadic Alzheimer's disease. The present stu dy examined the integrity of cholinergic and non-cholinergic systems in apo lipoprotein E-deficient, memory-impaired mice. Choline acetyltransferase ac tivity. hippocampal acetylcholine release, nicotinic and muscarinic (M1 and M2) receptor binding sites and acetylcholinesterase cell or terminal densi ty showed no signs of alteration in either three-month or 9.5-month-old apo lipoprotein E-deficient mice compared to controls. In contrast, long-term p otentiation was found to be markedly reduced in these mice, but increases i n the strength of stimulation induced the same level of long-term potentiat ion as that observed in controls. These alterations did not appear to be th e consequence of modifications in the binding properties of glutamatergic r eceptors (N-methyl-D-aspartate and [RS]-alpha-amino-3-hydroxy-5-methylisoxa zole propionic acid) but from defective regulation of the (RS)-alpha-amino- 3-hydroxy-5-methylisoxazole propionic acid receptor by phospholipase A2 act ivity. These results support the notion that apolipoprotein E plays a fundamental role in neuronal plasticity, which could in turn affect cognitive performan ce through imbalances in extra- and intracellular lipid homeostasis. (C) 19 99 IBRO. Published by Elsevier Science Ltd.