TAU BURDEN IN OREXINERGIC WAKE-PROMOTING NEURONS IN ALZHEIMER'S DISEASE IN COMPARISON TO CORTICAL BASAL DEGENERATION AND PROGRESSIVE SUPRANUCLEAR PALSY: A NEUROPATHOLOGICAL IMPLICATION IN SLEEP DISTURBANCES

Abstract

The neurobiological basis of sleep disturbances in tauopathies is currently unknown. Degeneration and/or malfunction of wake-and-sleep promoting neurons have been suspected to aggravate sleep dysfunction. AD patients experience fragmented sleep and daytime-somnolence. Progressive supranuclear palsy (PSP) patients show generalized sleep reductions (REM and non-REM); corticobasal degeneration (CBD) patients show variable profiles. Orexinergic wake-promoting neurons in perifornical nuclei (PFN) of the lateral hypothalamus excite monoaminergic and cholinergic nuclei of the arousal system and inhibit GABAergic activity of ventrolateral preoptic nuclei. We hypothesize that AD will have a greater overall neuronal loss and phopho-tau burden in PFN, compared to PSP and CBD. We used stereology to quantitatively investigate total and sub-population neuronal numbers, hyperphosphorylated tau burden, and the interdependence of these parameters in PFN in human. Serial 60-μm-thick sections encompassing the whole PFN in a sample of 7 AD, 6 CBD, and 2 PSP underwent double-labeled immunohistochemistry for Orexin A/hypocretin-1 (OrexinA, rabbit-polyclonal) and phosphorylated tau (CP13, pSer202) (Table 1). Stereology using the optical fractionator probe was performed to quantify the size of four neuronal subpopulations (sum=total neurons): orexinergic neurons bearing tau inclusions (ht-NCI), orexinergic neurons free of ht-NCI, orexinergic free neurons with ht-NCI, and orexinergic free neurons without ht-NCI. Krushkal-Wallis followed by a Nemenyi test revealed no significant difference in neuronal counts of markers of interest between AD, CBD, and PSP (Table 2). However, pairwise comparisons using Tukey and Kramer test revealed a significant difference (p= 0.02) in the proportion of total neurons with ht-NCI between AD and CBD, with AD showing the lower proportion (Figure 1–2). We also detected a significant difference (p= 0.0023) in the proportion of orexin positive neurons with ht-NCI between AD and CBD, with AD showing the lower proportion (Figure 3–4). Our unbiased stereological investigation detected moderate to high accumulation of phospho-tau in PFN in all three tauopathies. Tau burden in orexinergic neurons show a clear distinction between AD and CBD. Quantitative characterization of tau pathology and neuronal loss in sleep-related nuclei may inform on neurobiological basis of sleep disturbances. Further studies should focus on the role of degeneration of orexinergic neurons in exacerbating sleep fragmentation in AD patients. Proportion of Total Neurons with ht-NCI in the PFN. Proportion of Total Neurons with ht-NCI. Proportion of Active Neurons with ht-NCI in the PFN. Proportion of Active Neurons with ht-NCI.