Alterations to metabolic hormones in amyotrophic lateral sclerosis and frontotemporal dementia postmortem human tissue

Abstract

Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in the CNS is predominantly carried out within the hypothalamus, extra-hypothalamic CNS areas contain metabolic hormone receptors, including those for leptin (LEPR), insulin (INSR), and neuropeptide Y (NPY), indicating that they may play a role in biological processes underlying pathogenic disease processes. The status of these hormones within regions vulnerable in ALS/FTD is not well described. This study sought to determine whether the expression of these hormones and their receptors is altered in pathology-rich regions in cases of human FTD (superior frontal gyrus and insular cortex) and ALS (primary motor cortex and lumbar spinal cord) with TDP-43 pathology compared to matched healthy controls. LEPR mRNA was increased within the superior frontal gyrus of FTD cases and within primary motor cortex and lumbar spinal cord of ALS cases; INSR mRNA was increased in superior frontal gyrus and insular cortex of FTD cases. NPY protein was decreased in primary motor cortex and lumbar spinal cord of ALS cases. Our results demonstrate that metabolic hormones undergo complex alterations in ALS and FTD and suggest that these hormones could play critical roles in the pathogenesis of these diseases.

Keywords: amyotrophic lateral sclerosis; frontotemporal dementia; insulin; leptin; metabolism; neuropeptide Y (NPY); postmortem.

Figure 1.

Relative mRNA expression of LEPR (A) and INSR (B) in SFG and insular in controls compared to FTD cases (i) and in primary motor cortex and lumbar spinal cord in controls compared to ALS cases (ii). Red bars represent a significant effect of region. Blue bars represent a significant effect of diagnosis. Relative mRNA expression data were analyzed by linear mixed-effects models with a random intercept for each case, and Kenward-Roger adjusted post hoc contrasts. Data are presented as conditional means with 95% CIs. N = 5 cases per group, *P < .05.

Figure 2.

Relative mRNA expression of NPY (A) in SFG and insular in controls compared to FTD cases (i) and in primary motor cortex and lumbar spinal cord in controls compared to ALS cases (ii). Red bar represents a significant effect of region. Representative Western-blot images (B) and quantitation (C) of NPY and GAPDH protein expression in SFG and insular in controls and FTD cases (i) and in primary motor cortex and lumbar spinal cord in controls and ALS cases (ii). Relative mRNA expression data were analyzed by linear mixed-effects models with a random intercept for each case, and Kenward-Roger adjusted post hoc contrasts. Data are presented as conditional means with 95% CIs. Western-blot data were analyzed using 2-tailed unpaired t-test. Data are presented as means±SEM. N = 5 cases per group, *P < .05, **P < .01.

Figure 3.

Relative mRNA expression of GSK3β (A) and GSK3α (B) in SFG and insular in controls compared to FTD cases (i) and in primary motor cortex and lumbar spinal cord in controls compared to ALS cases (ii). Red bars represent a significant effect of region. Blue bar represents a significant effect of diagnosis. Representative Western-blot images (B) and quantitation (C) of GSK3β and GAPDH protein expression in SFG and insular in controls and FTD cases (i) and in primary motor cortex and lumbar spinal cord in controls and ALS cases (ii). Relative mRNA expression data were analyzed by linear mixed-effects models with a random intercept for each case, and Kenward-Roger adjusted post hoc contrasts. Data are presented as conditional means with 95% CIs. Western-blot data were analyzed using 2-tailed unpaired t-test. Data are presented as means±SEM. N = 5 cases per group, *P < .05.

Figure 4.

There are a range of clinical phenotypes related to altered metabolism that have previously been reported in patients with FTD and ALS. The current study examined changes to metabolic hormones and receptors in pathology-rich areas of the brain and spinal cord from patients with FTD and ALS, finding complex alterations at the protein and mRNA level. Abbreviations: BMI = body mass index, LepRB = leptin receptor, INSR = insulin receptor, NPY = neuropeptide Y, SFG = superior frontal gyrus, MCtx = motor cortex, Ins= insular cortex, LumSC = lumbar spinal cord. Figure created with BioRender.com.