Specific pattern of melanin-concentrating hormone (MCH) neuron degeneration in Alzheimer's disease and possible clinical implications

Study ObjectivesThe lateral hypothalamic area (LHA) is one of the key regions orchestrating sleep and wake control. It is the site of wake-promoting orexinergic and sleep-promoting melanin-concentrating hormone (MCH) neurons, which share a close anatomical and functional relation. The aim of the study was to investigate the degeneration of MCH neurons in Alzheimers disease (AD) and progressive supranuclear palsy (PSP), and relate the new findings to our previously reported pattern of degeneration of wake-promoting orexinergic neurons MethodsPost-mortem human brain tissue of subjects with AD, PSP and controls was examined using unbiased stereology. Double immunohistochemistry with MCH- and tau-antibodies on formalin-fixed, celloidin embedded tissue was performed. ResultsThere was no difference in the total number of MCH neurons between AD, PSP and controls, but a significant loss of non-MCH neurons in AD patients (p=0.019). The proportion of MCH neurons was significantly higher in AD (p=0.0047). No such a difference was found in PSP. In PSP, but not AD, the proportion of tau+ MCH neurons was lower than the proportion of tau+ non-MCH neurons (p=0.002). When comparing AD to PSP, the proportion of tau+MCH neurons was higher in AD (p<0.001). ConclusionsMCH neurons are more vulnerable to AD than PSP pathology. High burden of tau-inclusions, but comparably milder loss of MCH neurons in AD, together with previously reported orexinergic neuronal loss may lead to a hyperexcitability of the MCH system in AD, contributing to wake-sleep disorders in AD. Further experimental research is needed to understand why MCH neurons are more resistant to tau-toxicity compared to orexinergic neurons. STATEMENT OF SIGNIFICANCEThis is the first study to investigate the involvement of melanin-concentrating hormone (MCH) neurons in patients with Alzheimers disease and progressive supranuclear palsy. MCH neurons are key regulators of sleep and metabolic functions, and one of the major neuronal populations of the lateral hypothalamic area (LHA), but still underexplored in humans. Uncovering the pathology of this neuronal population in neurodegenerative disorders will improve our understanding of the complex neurobiology of the LHA and the interaction between MCH and orexinergic neurons. This new knowledge may open new strategies for treatment interventions. Further, this study represents a fundament for future research on MCH neurons and the LHA in tauopathies.