Abstracts for the 22nd Annual Meeting of the American Society for Neural Therapy and Repair

Abstract

A major feature of Alzheimer's disease (AD) is the loss of noradrenergic locus coeruleus (LC) projection neurons that mediate attention, memory, and arousal. However, the extent to which the LC projection system degenerates during the initial stages of AD remains unclear. To address this question, we performed tyrosine hydroxylase (TH) immunohistochemistry and unbiased stereology of LC neurons in tissue harvested postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI, a prodromal AD stage), or mild AD (n = 5-6/group). Stereologic estimates of total LC neuron number revealed a 30-35% decrease in aMCI versus NCI (p < 0.01) and a 45% loss of cells in mild AD compared to NCI (p < 0.01). Furthermore, LC fiber density was selectively reduced in the hippocampus compared to the neocortex of aMCI subjects, suggesting that coeruleohippocampal pathway degeneration marks the transition from normal cognition to prodromal disease. To examine the molecular pathogenic processes underlying LC neurodegeneration in aMCI, we combined laser capture microdissection with custom microarray technology to quantify gene expression patterns in individual TH-immunopositive neurons accessed from LC tissue samples. These studies revealed significant reductions in select functional classes of mRNAs regulating mitochondrial metabolism (e.g., cytochrome c1, cytochrome oxidase subunit 5a, p < 0.01), redox homeostasis (e.g., superoxide dismutase 2, glutathione peroxidase 1, p < 0.01), and cytoskeletal plasticity (e.g., microtubule-associated binding protein 1a, utrophin, p < 0.01) in both aMCI and AD subjects compared to NCI. Taken together, these observations show that LC projection system degeneration is a prominent feature during the transition from NCI to aMCI. In this regard, we are currently examining the extent of LC neuropathology in tissue from "preclinical AD" subjects who died with a clinical diagnosis of NCI but who displayed high postmortem Braak pathology. Targeting the noradrenergic LC system may present a novel disease-modifying strategy for cognitive protection in the elderly.