THE LOCUS COERULEUS: A LINK BETWEEN CEREBROVASCULAR AND NEURONAL PATHOLOGY IN PRECLINICAL ALZHEIMER’S DISEASE

Abstract

Noradrenergic locus coeruleus (LC) neuron loss is a major feature of Alzheimer's disease (AD). The LC projection system is the primary source of norepinephrine (NE) in the brain, where it modulates attention and memory in vulnerable regions such as prefrontal cortex (PFC). LC-mediated NE signaling is thought to play a role in blood brain barrier maintenance and neurovascular coupling, suggesting that LC degeneration may impact both cerebrovascular and AD pathophysiology. We have begun analyzing postmortem LC tissue samples from University of Kentucky AD Center subjects classified as no cognitive impairment (NCI) with Braak stage 0-II pathology at autopsy, NCI subjects with Braak stage III-V thought to be in a preclinical AD (PCAD) stage, and subjects with mild cognitive impairment (MCI) or mild AD. Pontine tissue blocks containing the LC were sectioned, immunostained with tyrosine hydroxylase (TH), and analyzed to estimate total LC neuron number (neuromelanin-containing LC neurons +/- TH). LC neuron number will be correlated with clinical pathologic variables and vascular pathology such as cerebral amyloid angiopathy (CAA). To model LC system degeneration in vivo, we stereotactically lesioned the PFC of 6 month old TgF344–19-AD rats using the noradrenergic immunotoxin, dopamine-β-hydroxylase (DBH)-saporin, or a control lesion (n = 12/group). Rats were tested behaviorally on the Barnes maze at 7 months and sacrificed for pathological analysis. Preliminary analysis of human samples (n = 6–7 cases/group) reveal a ∼20% loss of both total and TH+ LC neurons in PCAD (p = 0.08), a ∼30–35% loss of these neurons in MCI (p < 0.05), and a ∼45–50% loss of these neurons in AD (p < 0.01), compared to NCI. In our in vivo studies, DBH-saporin lesioned rats revealed significant deficits in spatial and working memory (p < 0.05). These animals also displayed increased markers for amyloidosis including CAA in PFC target fields. Pilot studies suggest that LC neurons display cell loss in preclinical AD compared to NCI. LC deafferentation of PFC in our rodent model results in memory deficits in increased vascular pathology. Targeting LC projection system dysfunction in preclinical AD may be a viable disease modifying strategy.