This proposal will provide the first cellular and molecular mechanistic profile of noradrenergic locus coeruleus (LC) projection system loss during the preclinical course of AD. LC neurons provide the sole source of norepinephrine (NE) to the hippocampus/medial temporal lobe (MTL) and cortex, where they regulate memory, attention and arousal. Notably, these cells are likely the initial site of neurofibrillary tagle (NFT) formation, suggesting that progressive LC neurodegeneration may help drive NFT formation in its target fields. However, the extent to which LC vulnerability impacts the onse of disease is unclear. Our preliminary studies show that LC neurons from subjects who died with amnestic mild cognitive impairment (aMCI) display significant cell loss compared to control subjects and that noradrenergic fiber density is selectively reduced in the hippocampus compared to cortical target fields during aMCI. These data suggest that selective LC neuronal loss and noradrenergic deafferentation of the hippocampus is a pathogenic preclinical event underlying the transition from normal cognition to prodromal AD. To understand the role of LC system degeneration in AD etiology, we will quantify LC cell loss and fiber density within the MTL and frontal cortex using rarely acquired cases of individuals who displayed no cognitive impairment at the time of death, but who were found to have moderate to high Braak scores that are predictive of AD;these cases are the tissue equivalent of a "pre- MCI" condition called preclinical AD (PCAD). Whether LC fiber loss directly impacts NFT formation in MTL target fields is unclear. Pilot studies in our laboratory revealed that chemical lesioning of the LC wth the compound DSP4 increased NFT pathology in hippocampal CA1 neurons of the 3xTg-AD mouse, providing novel mechanistic evidence that LC degeneration propagates NFT pathology. To explore this mechanism, we used custom microarrays to analyze gene expression differences in CA1 neurons microdissected from control and DSP4-treated 3xTg-AD mice. Quantitative analysis revealed that noradrenergic deafferentation in DSP4-treated mice resulted in a pronounced 80% down- regulation of the transcription factor nuclear respiratory factor 1 (NRF1) in CA1 neurons. Moreover, pathway analysis unveiled a striking pattern wherein several NRF1 transcriptional targets were also down-regulated, including functional classes of transcripts regulating calcium-mediated neuronal excitabilit (e.g., GluR2 AMPA receptor) and mitochondrial biogenesis (e.g., cytochrome oxidase V). Subsequent pilot studies showed that NRF1 expression is tightly regulated by NE and that NRF1 is selectively reduced in the hippocampus compared to frontal cortex in aMCI subjects, tracking with the pattern of LC deafferentation. Therefore, our hypothesis is that LC projection system degeneration potentiates NFT pathology in MTL neurons during PCAD by disrupting NRF1-mediated calcium and mitochondrial homeostasis. To gain a better understanding of the effects of NE depletion on MTL neurofibrillary degeneration during the preclinical course of AD, we will combine in vivo manipulations of the 3xTg-AD mouse with exploratory microarray and pathway analysis of CA1 neurons. Altogether, this proposal will advance our understanding of fundamental mechanisms underlying multisystem deafferentation within the LC-MTL memory circuit, resulting in new information about disease etiology and new targets for timely diagnostic and therapeutic approaches.
Alzheimer's disease (AD) research has become increasingly focused on the earliest neurodegenerative changes involved in disease pathogenesis. This proposal follows up on exciting preliminary studies to explore the potential etiologic role of locu coeruleus (LC) forebrain projection system degeneration in AD. To do so, LC cell loss and selective deafferentation of the medial temporal lobe (MTL) will be examined in individuals with preclinical AD (PCAD) who were classified antemortem as cognitively normal but who displayed high levels of AD pathology at autopsy. Furthermore, based on our in vivo pilot data, we will test the hypothesis that LC fiber loss potentiates tangle pathology in MTL neurons by disrupting nuclear respiratory factor 1 regulation of calcium and mitochondrial homeostasis. This proposal will positively impact the field by providing new insights into PCAD pathophysiology and new targets for disease modifying therapies.
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