Noradrenergic locus coeruleus (LC) neuron loss is a feature of Alzheimer’s disease (AD). The LC is the primary source of norepinephrine (NE) in the forebrain, where it modulates attention and memory in vulnerable cognitive regions such as prefrontal cortex (PFC) and hippocampus. Furthermore, LC-mediated NE signaling is thought to play a role in blood-brain barrier (BBB) maintenance and neurovascular coupling, suggesting that LC degeneration may impact the high comorbidity of cerebrovascular disease (CVD) and AD. However, the extent to which LC projection system degeneration occurs in the earliest stages of AD and the physiological consequences of this phenomenon is not fully characterized to date. To address these issues, we analyzed LC tissue samples from University of Kentucky AD Center (UKADC) subjects who died with a premortem diagnosis of no cognitive impairment (NCI) and Braak stages 0-II at autopsy, NCI subjects with Braak stages III-V thought to be in a preclinical AD (PCAD) stage, and subjects with mild cognitive impairment (MCI) or mild AD. Paraffin-embedded pontine tissue blocks containing the LC were cut at 20μm, immunostained with tyrosine hydroxylase (TH, a marker for NE synthesis), and analyzed to estimate total TH-positive LC neuron number. We measured a significant ~40-55% loss of LC neuron numbers in MCI and AD compared to NCI, whereas the mild ~25% LC neuron loss observed in PCAD did not reach significance. However, the topographical, rostrocaudal extent of LC cell loss in PCAD was significantly different from NCI and MCI. Moreover, LC cell loss correlated with premortem global cognition across the diagnostic groups. Studies were also performed to compare additional LC neuronal pathologies (phospho-tau and DNA/RNA oxidative damage markers) across the diagnostic groups. A significant ~15-30% increase in phospho-tau was observed in PCAD and MCI compared to NCI. DNA/RNA oxidative damage was significantly increased by ~25-40% in MCI and AD compared to NCI and PCAD. LC phospho-tau pathology correlated with Braak stage, whereas LC oxidative damage correlated with premortem global cognitive performance . Finally, while LC neuron number did not correlate with scores of global arteriosclerosis or microinfarcts, pontine arteriosclerosis severity was increased by two-fold in MCI and AD. To model the relationship between LC projection system degeneration and forebrain neuronal and vascular pathology in vivo, we stereotactically lesioned LC projection neurons innervating the PFC of the TgF344-19 rat model of AD (aged 6 months) using the noradrenergic immunotoxin, dopamine-β-hydroxylase IgG-saporin (DBH-sap), or an untargeted control IgG saporin (IgG-sap). DBH-sap lesioned animals performed significantly worse on the Barnes maze task and displayed increased amyloid and inflammatory pathology, as well as evidence for vessel remodeling and BBB leakage, compared to IgG-sap control animals. Taken together, these data compiled in my dissertation shed light on the multifactorial noradrenergic pathways contributing to neuronal and vascular pathologies during the onset of AD.
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