A post‐mortem study of melanin‐concentrating hormone (MCH) neurons in Alzheimer’s disease and progressive supranuclear palsy: The complex degeneration pattern of the lateral hypothalamic area

Abstract

AbstractBackgroundMelanin‐concentrating hormone neurons (MCH) are a key component of the subcortical brain circuits controlling sleep and wake states, and integrating them with other vital functions like motivated and feeding behavior into a 24‐hour circadian rhythm. Together with orexinergic neurons (OX), they represent the major neuronal population of the lateral hypothalamic area (LHA). Our group previously reported a profound degeneration of OX neurons in Alzheimer's disease (AD), and a reduction of OX production in progressive supranuclear palsy (PSP). 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.MethodPost‐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.ResultThere was no significant 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).ConclusionHigh 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. This 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, which reflects a specific vulnerability of these neurons to AD pathology. 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. Further experimental research is needed to understand the molecular pathways involved in the specific vulnerability of MCH neurons in AD.