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.

Keywords: Alzheimer’s disease; Huntington’s disease; amyotrophic lateral sclerosis; fronto-temporal dementia; hypothalamus; neurodegeneration; weight loss.

Figure 1

Location of the hypothalamus and its nuclei. Location of the hypothalamus in mouse (A) and human (B) brains. The panel (C) schematically presents the major hypothalamic nuclei and their involvement in energy homeostasis. For simplicity, cocaine and amphetamine regulated transcript (CART) expression was omitted from POMC neurons (noted POMC) and NPY expression was omitted from AgRP neurons (noted AgRP). Abbreviations: 3V, Third ventricle; ARC, Arcuate Nucleus; DM, Dorsomedial Nucleus; LHA, Lateral Hypothalamus Area; PVN, Paraventricular Nucleus; POMC, Pro-opiomelanocortin; AgRP, Agouti related peptide; NPY, neuropeptide Y; Neu., Neurotensin; ORX, Orexin; MCH, Melanin Concentrating Hormone; OXT, Oxytocin; TRH, Thyrotropin-releasing hormone; CRH, Corticotropin-releasing hormone; BBB, Blood Brain barrier.

Figure 2

Hypothalamic involvement in Alzheimer’s disease (AD). The main neuropathological changes identified in the hypothalamus in postmortem tissue of AD patients are indicated. The pathological aggregates (either amyloid plaques or NFTs) are shown as black diamonds mostly in PVN and LHA. The dashed lines indicate a reduced effect. Loss of orexin neurons and a slight increase of MCH neurons have been reported. Abbreviations as in Figure 1, except: NFT, Neurofibrillary tangle; ROS, Reactive oxygen species; Aβ, Amyloid Beta; BACE1, beta secretase 1; APP, Amyloid precursor protein.

Figure 3

Hypothalamic involvement in Huntington’s disease (HD). The main neuropathological changes identified in the hypothalamus in postmortem tissue of HD patients and mouse models are indicated. Loss of orexin, oxytocin, vasopressin and NPY neurons have been reported. Abbreviations as in Figure 1.

Figure 4

Hypothalamic involvement in fronto-temporal dementia (FTD; behavioral variant). The main neuropathological changes identified in the hypothalamus in postmortem tissue of bv-FTD patients are indicated. The pathological aggregates (TDP-43 or TAU aggregates) are shown as black diamonds mostly in LHA and DM. Abbreviations as in Figure 1.

Figure 5

Hypothalamic involvement in Amyotrophic Lateral Sclerosis (ALS). The main neuropathological changes identified in the hypothalamus in postmortem tissue of ALS patients and mouse models are indicated. The pathological aggregates (TDP-43 inclusions) are shown as black diamonds mostly in LHA. Of note, the loss of POMC and increased AgRP expression were only shown in mouse models. Abbreviations as in Figure 1.