Autor:innen:
Mihovil Mladinov, San Francisco (United States)
Jun Oh, San Francisco (United States)
Cathrine Petersen, San Francisco (United States)
Felipe Luiz Pereira, San Francisco (United States)
Caroline Lew, San Francisco (United States)
Chia-Ling Tu, San Francisco (United States)
Wenhan Chang, San Francisco (United States)
Thomas C. Neylan, San Francisco (United States)
Lea T. Grinberg, San Francisco (United States)
Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) are characterized by distinct and severe sleep-wake disorders. The lateral hypothalamic area (LHA) is one of the key regions regulating sleep and wake states. It is the site of wake-promoting orexinergic and sleep-promoting melanin-concentrating hormone neurons (MCH), which share a close anatomical and functional relation. In this report we provide for the first time a comprehensive and quantitative morphological study of MCH neurons in patients with AD, PSP and normal controls, and relate the findings to our previously reported pattern of orexinergic (ORX) neuron degeneration. We examined postmortem brain samples using unbiased stereology and performed high-plex spatial protein analysis of paraffin embedded slides.
The stereological analysis showed high burden of tau-inclusions, but comparably milder loss of MCH neurons in AD, with no significant difference in the total number of MCH neurons between AD, PSP and controls. There was a significant loss of non-MCH neurons in AD patients. On the other side, we previously reported a profound ORX neuronal loss in AD. The lack of inhibitory effect of ORX and tau-driven dysfunction of MCH neurons, may contribute to the well-known impairment of vigilance, reduction of NREM sleep and REM sleep disruption in AD. In contrast, we found virtually no involvement of MCH neurons in PSP. Clinically, PSP features a hyperarousal state, indicating that the activity of the arousal system prevails over a deficient sleep promoting system. We conclude that the involvement of other sleep promoting nuclei contributes to the insomnia in PSP. The spatial multiplex protein profiling showed a differential expression of cell-death related proteins and a specific pattern of tau-phosphorylation through progressive AD. MCH compared to ORX neurons accumulated higher tau levels, supporting our observation of a relative resistance of MCH cells to cell death even in advanced stages of AD.