Hemoglobin mRNA Changes in the Frontal Cortex of Patients with Neurodegenerative Diseases

Abstract

Background: Hemoglobin is the major protein found in erythrocytes, where it acts as an oxygen carrier molecule. In recent years, its expression has been reported also in neurons and glial cells, although its role in brain tissue remains still unknown. Altered hemoglobin expression has been associated with various neurodegenerative disorders. Here, we investigated hemoglobin mRNA levels in brains of patients affected by variant, iatrogenic, and sporadic forms of Creutzfeldt-Jakob disease (vCJD, iCJD, sCJD, respectively) and in different genetic forms of prion diseases (gPrD) in comparison to Alzheimer's disease (AD) subjects and age-matched controls.Methods: Total RNA was obtained from the frontal cortex of vCJD (n = 20), iCJD (n = 11), sCJD (n = 23), gPrD (n = 30), and AD (n = 14) patients and age-matched controls (n = 30). RT-qPCR was performed for hemoglobin transcripts HBB and HBA1/2 using four reference genes for normalization. In addition, expression analysis of the specific erythrocyte marker ALAS2 was performed in order to account for blood contamination of the tissue samples. Hba1/2 and Hbb protein expression was then investigated with immunofluorescence and confocal microscope analysis.Results: We observed a significant up-regulation of HBA1/2 in vCJD brains together with a significant down-regulation of HBB in iCJD. In addition, while in sporadic and genetic forms of prion disease hemoglobin transcripts did not shown any alterations, both chains display a strong down-regulation in AD brains. These results were confirmed also at a protein level.Conclusions: These data indicate distinct hemoglobin transcriptional responses depending on the specific alterations occurring in different neurodegenerative diseases. In particular, the initial site of misfolding event (central nervous system vs. peripheral tissue)—together with specific molecular and conformational features of the pathological agent of the disease—seem to dictate the peculiar hemoglobin dysregulation found in prion and non-prion neurodegenerative disorders.In addition, these results suggest that gene expression of HBB and HBA1/2 in brain tissue is differentially affected by distinct prion and prion-like aggregating protein strains. Validation of these results in more accessible tissues could prompt the development of novel diagnostic tests for neurodegenerative disorders.

L-Arginine Exerts Excellent Anti-Stress Effects on Stress-Induced Shortened Lifespan, Cognitive Decline and Depression

“…As both Hba and Hbb are co-localized within the mitochondrion of neurons and are closely associated to maintain the neuronal mitochondrial function as well as survival of neurons [ 47 ], we speculate that Arg protects neurons by maintaining the neuronal mitochondrial function. An increase in the expression of Hba and Hbb reportedly has therapeutic effects against neurodegenerative disease, and increasing evidence suggests that a deficiency in these chains in the brain is associated with neurodegenerative disease [ 53 , 54 ]. Our results suggest that Arg may also be important in protecting the brain from neurodegenerative diseases such as Alzheimer’s disease.…”

Brain aging: A Ianus‐faced player between health and neurodegeneration

“…Furthermore, we recently reported a strong down‐regulation of the genes related to both chains of hemoglobin, HBA1/2 and HBB , in the brain of AD patients (Vanni et al, ).…”

Growth Hormone and Neuronal Hemoglobin in the Brain—Roles in Neuroprotection and Neurodegenerative Diseases

“…Aβ activates a molecular response pathway that leads to strong downregulation of Hb gene expression in the brain, which could damage cells due to defective oxygen homeostasis ( 144 ). Reduced concentrations of the Hb α-chain and β-chain proteins have been detected in neurons with granular or punctuate hyperphosphorylated tau deposits, in AD neurons with tangles in the hippocampus and frontal cortex, and in AD neurons in the amygdala ( 135 ).…”

“…Furthermore, altered iron metabolism has been observed in the CNS of patients with a variety of neurodegenerative diseases, including AD. The concomitant occurrence of a decrease in local Hb expression in AD and the increased level of free iron, which is highly toxic due to the creation of reactive oxygen species (144), is possibly coincidental, although it indicates the importance of iron metabolism. Epidemiologic studies have suggested strong associations between anemia, decline of cognitive function, and AD, with an inverse relationship noted between Hb and AD (145)(146)(147).…”