Hypothalamic Alterations in Neurodegenerative Diseases and Their Relation to Abnormal Energy Metabolism

Abstract

Neurodegenerative diseases (NDDs) are disorders characterized by progressive deterioration of brain structure and function. Selective neuronal populations are affected leading to symptoms which are prominently motor in amyotrophic lateral sclerosis (ALS) or Huntington’s disease (HD), or cognitive in Alzheimer’s disease (AD) and fronto-temporal dementia (FTD). Besides the common existence of neuronal loss, NDDs are also associated with metabolic changes such as weight gain, weight loss, loss of fat mass, as well as with altered feeding behavior. Importantly, preclinical research as well as clinical studies have demonstrated that altered energy homeostasis influences disease progression in ALS, AD and HD, suggesting that identification of the pathways leading to perturbed energy balance might provide valuable therapeutic targets Signals from both the periphery and central inputs are integrated in the hypothalamus, a major hub for the control of energy balance. Recent research identified major hypothalamic changes in multiple NDDs. Here, we review these hypothalamic alterations and seek to identify commonalities and differences in hypothalamic involvement between the different NDDs. These hypothalamic defects could be key in the development of perturbations in energy homeostasis in NDDs and further understanding of the underlying mechanisms might open up new avenues to not only treat weight loss but also to ameliorate overall neurological symptoms.

Paradox of amyotrophic lateral sclerosis and energy metabolism

“…Of relevance, hypothalamic atrophy was identified in ALS in both symptomatic and presymptomatic cohorts and correlated with body mass index 8 9. Similar findings have been identified in frontotemporal dementia10 11 and suggest that changes in neural pathways and central factors may have a pivotal role in controlling food intake and energy metabolism,12 either as pathogenic drivers or as adaptive mechanisms. Disentangling pathogenic pathways from compensatory responses will be challenging in future studies as it seems likely that the body tries to adapt to the imbalance of increased energy metabolism by rewiring hypothalamic neural circuits leading to increased food intake 13.…”

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

“…The spatiotemporal progression of NFTs from the entorhinal cortex and the hippocampus to the isocortical areas has been shown to be correlated with cognitive deficits [85], supporting a pivotal role for Tau pathology and spreading in AD-related memory impairments [86]. Interestingly, hypothalamus that plays a key role in the central control of energy metabolism has been also shown to display alterations in AD [87, 88]. In a study investigating 28 patients with AD, 22 patients showed plaques and NFTs in the hypothalamus [87].…”

Abnormal Photic Entrainment to Phase-Delaying Stimuli in the R6/2 Mouse Model of Huntington's Disease, despite Retinal Responsiveness to Light

“…stein and Amir, 1999). Hypothalamic regions are also good candidates as alterations have been reported both in HD patients and animal models (Vercruysse et al, 2018;Cheong et al, 2019). The dorsomedial hypothalamic nucleus is responsible for relaying circadian temporal information from the SCN to the locus ceruleus (Gompf and Aston-Jones, 2008), and excitotoxic lesion of this region has been reported to decrease behavioral circadian rhythms including locomotor activity (Chou et al, 2003).…”