Hypothalamic melanin‐concentrating hormone neurons, key sleep cycle modulators, degenerate early in Alzheimer’s disease

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AbstractBackgroundSleep disorders represent one of the leading causes of life impairment and a major therapeutic challenge in patients with Alzheimer’s disease (AD) and tauopathies. However, the disease specific neurobiological basis of these sleep disturbances remains mostly elusive. Melanin‐concentrating hormone (MCH) neurons are a conserved neuronal population in the lateral and posterior hypothalamus with critical sleep/wake and metabolic control functions in animals, but largely underexplored in humans. Here, we used unbiased stereology to examine the involvement of MCH neurons in Alzheimer’s disease (AD) as a 3R‐tauopathy, and progressive supranuclear palsy (PSP) as a 4R‐tauopathy featuring hyperinsomnia.MethodWe used unbiased stereology to quantify total and MCH‐positive neuronal numbers and tau burden in the region of interest (ROI) of 5 AD and 6 PSP brains (for detailed demographics see Table 1). Data were analyzed using Wilcoxon signed rank and Mann‐Whitney U tests.ResultBoth AD and PSP subjects show significant neuronal tau‐burden in the ROI. There was no statistically significant difference in the absolute number of MCH‐neurons and non‐MCH‐neurons (Figure 1), or proportion of MCH neurons in the total neuronal population between AD (26.5%) and PSP (24.9%). Whereas there was no difference in the proportion of tau+ non‐MCH neurons between AD and PSP, the proportion of tau+ MCH‐neurons was significantly higher in AD relative to PSP (p=0.0043) (Figure 2). Contrary to AD, where MCH and non‐MCH neurons had similar tau‐burden (18.8% and 17.1%, respectively), in PSP there was a significantly lower involvement of MCH‐neurons (4.9%) in comparison to the total neuronal population (19.9%, p=0.0313) (Figure 2). In the PSP group there was a positive correlation between Braak stages and the proportion of tau+ MCH neurons (p=0.023), but not total tau+ neurons.ConclusionOur preliminary data show a trend for lower neuronal numbers in AD and in PSP, lower neuronal numbers correlated with higher Braak stages. Together, it suggest an early vulnerability of MHC to AD and a moderate vulnerability to PSP. We are analyzing further cases to increase the power of analysis. Different involvement of MCH‐neurons in AD and PSP may reflect the specific patterns of sleep disorders in those tauopathies.