Altered locus coeruleus activity and neurochemistry in the presence of Alzheimer's disease-like hyperphosphorylated tau pathology.

Abstract

The locus coeruleus (LC), the main source of norepinephrine (NE) in the brain, develops tau pathology prior to other brain regions and later degenerates in Alzheimer's disease (AD). Emergence of prodromal symptoms before cognitive impairment is evident, such as anxiety, agitation, and sleep disturbances, parallels development of hyperphosphorylated tau in the LC. Although pathogenic tau can alter the activity of other neurons, and noradrenergic dysfunction likely contributes to prodromal AD symptoms, the consequences of hyperphosphorylated tau on LC function are unknown. TgF344-AD rats, which develop hyperphosphorylated tau in the LC prior to other brain regions, and wild-type (WT) littermates aged 6 and 15 months (3-10 rats/group) were used. Baseline and footshock (0.5ms and 5ms 10mA)-evoked single unit LC activity (27-111 neurons/group) were recorded in chloral hydrate anesthetized rats. LC sections from duplicate groups of rats were immunostained for tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) to proxy NE synthesis capacity, NE transporter (NET) to assess somatodendritic LC integrity and NE uptake, monoamine oxidase A (MAOA) to evaluate NE metabolism, galanin to measure peptide co-transmitter levels, and GAD67 to investigate local inhibitory networks (3-4 slices/animal, 2-7 animals/group). Grayscaled fluorescence was measured in ImageJ. Electrophysiology revealed a trend towards increased LC baseline firing rates in WT and TgF344-AD rats at 15 months vs 6 months, with no genotype differences. Footshock-evoked LC activity tended to be exaggerated in TgF344-AD rats at 6 months, but blunted or unchanged at 15 months compared to WT. Immunofluorescence indicated decreased NET in TgF344-AD rats at 6 months, with both genotypes showing a reduction at 15 months compared to younger animals. GAD67 was significantly higher in 15-month animals compared to 6 months, with no genotype differences. No significant effects of genotype or age were found for MAOA, DBH, or galanin. These results suggest early LC dysfunction that coincides with the onset of hyperphosphorylated tau pathology. Further studies investigating the time course of LC dysfunction in AD, as well as therapies aimed at correcting these abnormalities, are warranted.