1- Introduction

2- Expression and function of hemoglobins in neural tissues

3- Possible pitfalls of detecting Hb mutations and cognitive deficits in thalassemia carriers

4- Protective roles of intraneuronal Hb’s in AD and aging?

5- Any role of blood contamination in studies of Hb’s in brain?

6- Hb chains and α-synuclein

7- High levels of extracellular Hb in circulation may facilitate further Hb entry into neuropil via damaging the BBB

8- Neurotoxicity of Free Hb diffused into the brain in AD

9- Abnormal levels of Hb are detrimental for brain health and cognition

10- Hemorphin’s and Alzheimer’s disease

11- Erythropoietin/Hb axis with particular relevance to treatment of AD

12- Conclusions and future prospects

References

Abstract

Hemoglobins (Hbs) are heme-containing proteins binding oxygen, carbon monoxide, and nitric oxide. While erythrocytes are the most well-known location of Hbs, Hbs also exist in neurons, glia and oligodendroglia and they are primarily localized in the inner mitochondrial membrane of neurons with likely roles in cellular respiration and buffering protons. Recently, studies have suggested links between hypoxia and neurodegenerative disorders such as Alzheimer Disease (AD) and furthermore suggested involvement of Hbs in the pathogenesis of AD. While cellular immunohistochemical studies on AD brains have observed reduced levels of Hb in the cytoplasm of pre-tangle and tangle-bearing neurons, other studies on homogenates of AD brain samples observed increased Hb levels. This potential discrepancy may result from differential presence and function of intracellular versus extracellular Hbs. Intracellular Hbs may protect neurons against hypoxia and hyperoxia. On the other hand, extracellular free Hb and its degradation products may trigger inflammatory immune and oxidative reactions against neural macromolecules and/or damage the blood-brain barrier. Therefore, biological processes leading to reduction of Hb transcription (including clinically silent Hb mutations) may influence intra-erythrocytic and neural Hbs, and reduce the transport of oxygen, carbon monoxide and nitric oxide which may be involved in the (patho)physiology of neurodegenerative disorders such as AD. Agents such as erythropoietin, which stimulate both erythropoiesis, reduce eryptosis and induce intracellular neural Hbs may exert multiple beneficial effects on the onset and course of AD. Thus, evidence accumulates for a role of Hbs in the central nervous system while Hbs deserve more attention as possible candidate molecules involved in AD.

Introduction

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder comprising a complex etiopathogenesis, which ultimately leads to progressive loss of memory and other cognitive functions (Burns and Iliffe, 2009). AD has a devastating impact on global human health and economy and has an increasing prevalence due to an aging society (Burns and Iliffe, 2009; Dementia Fact Sheet, 2016). As no efficient treatment exists, there is a great need for improving our understanding of the etiopathogenesis and pathophysiology, which will hopely inform innovative strategies for intervention. Until now, a plethora of scientific experiments were conducted to discover novel treatments of AD and many clinical trials were conducted with several candidate molecules, yet few drugs with limited activity exist in the armamentarium against AD. Hence, illuminating novel pathways of pathogenesis and discovery of new therapeutic molecules in AD is an urgent and essential need. The current manuscript reviews the available evidence on hemoglobins (Hbs) and their links with AD. We will illustrate that i) the presence of hemoglobin chains was recently discovered in neurons (Biagioli et al., 2009), ii) Hbs play key roles in the pathophysiologies of a range of disorders, iii) modulation of Hbs is known to have significant impact on cellular functions (e.g. in cellular respiration and buffering oxygen radicals). Based on published findings on Hbs, we propose that i) neuronal intracytoplasmic and mitochondrial Hbs may exert protective functions in AD, ii) aberrations in structure (e.g. undetected minor thalassemias and hemoglobinopathies), translation, or amount of neuronal Hbs may play a role in the etiology of AD, iii) structural abnormalities of Hbs may trigger supraphysiological accumulation of Hbs in mitochondria and cause pathological interactions with β-amyloid and α-synuclein, and iv) extracellular Hb released from degraded red blood cells (RBC) may induce toxicity, disruption and/or degeneration of neurons as well as the blood brain barrier (BBB) in AD.