EVIDENCE FOR NORMAL AGING OF THE SEPTOHIPPOCAMPAL CHOLINERGIC SYSTEM IN APOE (- -) MICE BUT IMPAIRED CLEARANCE OF AXONAL DEGENERATION PRODUCTS FOLLOWING INJURY/

The association of the epsilon 4 allele of apoE with increased risk fo r Alzheimer's disease (AD) and with poor clinical outcome after certai n acute brain injuries has sparked interest in the neurobiology of apo E. ApoE (-/-) mice provide a tool to investigate the role of apoE in t he nervous system in vivo. Since integrity of the basal forebrain chol inergic system is severely compromised in AD, with severity of dysfunc tion correlating with apoE4 gene dosage, the present study tested the hypothesis that apoE is required to maintain the normal integrity of b asal forebrain cholinergic neurons (BFCNs). Histological and biochemic al analyses of the septo-hippocampal cholinergic system were performed in apoE (-/-) mice during aging and following injury. Using unbiased quantitative methods, there was little or no evidence for defects in t he septo-hippocampal cholinergic system, as assessed by p75(NTR)-immun oreactive neuron number and size in the medial septum, cholinergic fib er density in the hippocampus, and choline acetyltransferase activity in the hippocampus, cortex, and striatum in aged apoE (-/-) mice (up t o 24 months of age) as compared to age-matched wild-type mice of the s ame strain. In addition, cholinergic neuronal survival and size follow ing fimbria-fornix transection in apoE (-/-) mice did not differ from controls. However, following entorhinal cortex lesion, there was persi stence of degeneration products in the deafferented hippocampus in apo E (-/-) mice. These data suggest that although apoE is not required fo r the maintenance of BFCNs in vivo, it may play a role in the clearanc e of cholesterol-laden neurodegeneration products following brain inju ry. (C) 1998 Academic Press.