Perspective associated virus-HIF-1α inhibits neuronal in Alzheimer’s disease: of the hippocampus induced by Aβ peptides. HIF-1 increases glycolysis and the hexose monophosphate shunt, maintains effects of hypoxia inducible factors the mitochondrial membrane potential and cytosolic accumulation of cytochrome C, thereby inactivating caspase-9 and caspase-3, * Halimatu Hassan, Ruoli Chen and thus prevents neuronal death in the AD brain. Oxidative damage, caused by Aβ peptide Alzheimer’s disease (AD), a common (Lall et al., 2019). Neuroinflammation plays induces mitochondrial dysfunction, which is neurodegenerative disease, afflicts 26 million a detrimental role in AD pathogenesis, as a major characteristic of neuronal apoptosis. people worldwide currently with projection of a microglia depletion by colony stimulating factor Additional pathological features of AD are fourfold increase in this figure by the year 2050 receptor 1 inhibitors improves AD symptoms in astrocyte activation and reduced glucose (Brookmeyer et al., 2018). The majority of AD in vivo (Rawlinson et al., 2020). metabolism in some selected brain areas. cases (95%) are sporadic, having the late-onset Cells respond to hypoxia by stabilizing hypoxia Maintenance of HIF-1α levels reverses Aβ affecting those over 65 years old. About 15% inducible factor (HIF), a key transcription factor peptide-induced glial activation and glycolytic among those 65 years and older suffer from regulating homeostasis. The HIF levels changes, thus mediating a neuroprotective AD, and the incidence of AD is close to 50% for in cells are directly regulated by four oxygen- response to Aβ peptide by maintaining those aged over 85 years (Brookmeyer et al., sensitive hydroxylases: 3 prolyl hydroxylases metabolic integrity. HIF-1 is the major 2018). There are a number of changes in the (PHD1-3) and 1 asparaginyl hydroxylase, factor transcription factor that increases ageing brain, such as reduced cerebral blood inhibiting HIF (Chen et al., 2018). Both oxygen network density and improves blood circulation flow, white matter changes, iron overload, and 2 oxoglutarate are substrates of these in living tissue by regulating proteins expression and neuroinflammation (Chen et al., 2010). enzymes, while iron and ascorbate are co- such as erythropoietin, glucose transporter The reduction of cerebral blood flow leads to factors. In a normal oxygen environment, HIF 1, 3 and vascular endothelial growth factor. hypoperfusion, thus causing cerebral hypoxia, hydroxylase is active and degrades the HIF-α Erythropoietin is able to block the Aβ generated which is a common vascular component among subunit. Yet, in a reduced oxygen environment, neuronal apoptosis, while glucose transporter the AD risk factors. Prolonged and severe the absence of oxygen as a substrate, renders 1, 3 increase glucose transport into brain nerve hypoxia can cause neuronal loss and memory the HIF hydroxylases inactive, thus the HIF-α cells. All in all, HIF-1 participates in hypoxia- impairment. It has been understood that subunit accumulates and binds to the HIF-α induced adaptive reactions to restore cellular patients with are at risk of AD. Up to subunit, forming the HIF molecule (Figure homeostasis, and postpone the progression of 1/3 of stroke survivors suffer from post stroke 1). The stabilization of HIF upregulates the AD (Figure 1). (Mijajlovic et al., 2017). The most expression of hundreds of HIF targeted genes A group of agents which can upregulate common cause of post stroke dementia are that help cells and tissue survival in hypoxia, , AD and mixed dementia. the HIF levels in normoxia are termed as as well as a number of apoptotic genes, such hypoxia mimetic agents (Chen et al., 2018). Hypoxia is a condition where oxygen tensions as Bax, BNIP3 (Figure 1). HIF-1α is ubiquitously These agents include HIF hydroxylase are below the normal level of tissue oxygen expressed, and appears the most active isoform inhibitors and iron chelators. The inhibition tension (Chen et al., 2018). Hypoxia can be during short periods (2–24 hours) of intense of HIF hydroxylase not only exerts pleiotropic classified as acute, intermittent, chronic hypoxia or anoxia (< 0.1% O2) in some cell lines. neuroprotective effects as a consequence according to the duration; mild, moderate, HIF-2α is more tissue specific and is emerging of HIF induction, but also has anti-oxidant severe according to the extent. The duration as a distinct entity in target gene induction in and anti-inflammatory effects (Figure 1). HIF and extent of hypoxia in different cells dictate the vascular endothelia cells, and is known as hydroxylase inhibition, which engages multiple their beneficial or detrimental effects on the an endothelium specific HIF-α isoform. HIF-2α downstream effector pathways, is a promising cells. Severe and/or chronic hypoxia, impair is active under mild or physiological hypoxia, therapeutic intervention that can challenge the delivery of oxygen, affect cellular metabolism, and continues to be active even after 48–72 heterogeneity in AD pathophysiology present ATP production, Ca2+ homeostasis, and lead to hours of hypoxia. HIF-2α shares 48% amino in humans. Because the HIF hydroxylase reactive oxygen species (ROS) formation and acid homology with HIF-1α, and binds to similar inhibition leverages endogenous adaptive (Chen et al., 2018). While mild, promoter sites but differs in the cofactors programs, the breadth of the response will not moderate and/or intermittent hypoxia have it recruits. HIF-1 and HIF-2 have largely lead to an increased likelihood of toxicity. It is been found to induce protective adaptations in overlapping but also some non-redundant important to emphasize that HIF hydroxylase the brain (Lall et al., 2019). functions. In some contexts, HIF-1α plays a key inhibition does not equal HIF activation. HIFs role in initial response to hypoxia whereas HIF- In the AD process, hypoxia enhances a shift in are only one of a number of growing substrates 2α drives the hypoxic response during chronic known to modulate via HIF hydroxylase (Chen amyloid precursor protein processing toward hypoxic exposure. the amyloidogenic pathway and down‐regulates et al., 2018). To our best knowledge, there the function of α‐secretase. Hypoxia inhibits the It has been revealed by sequence analysis and are no studies applying PHD inhibitors for AD expression and activity of an amyloid‐degrading gel shift studies that HIF-1 binds to β‐secretase treatment. Li et al. (2018) applied FG4592 for peptidase ‘neprilysin’ in cortical of rat, 1 (BACE1) promoter, and that overexpression of the treatment of Parkinson’s disease both in increasing the accumulation of amyloid beta HIF-1α in neuronal cells increases BACE1 mRNA vitro and in vivo. FG4592, a HIF PHD inhibitor, (Aβ) peptides in the affected regions. It has and protein levels, and down-regulation of HIF- is currently used for anaemia treatment in been shown that hypoxia interplays with Aβ 1α reduces the levels of BACE1. It has been patients with chronic kidney disease. Li et peptide aggravating the neuronal death. There observed that HIF-1 binds to the promoter of al. (2018) concluded that FG4592 could be is an increase vulnerability of hippocampal anterior pharynx-defective phenotype (APH- potentially used for treating Parkinson’s disease neurons to Aβ peptide toxicity during hypoxia. 1) to up-regulate its expression, leading to an by improving the neuronal mitochondrial Calcium dyshomeostasis is a fundamental increase in γ-cleavage of amyloid precursor function under oxidative stress. mechanism in AD pathogenesis. Aβ interaction protein and Notch. HIF‐1 also binds to gene Iron chelation has been widely studied to treat with the plasma membrane leads to elevated promoter of neprilysin and suppresses its neurodegenerative diseases, including AD and cytoplasmic Ca2+ concentrations and enhances transcription (Lall et al., 2019). Parkinson’s disease, as iron accumulation is excitation of . Chronic hypoxia enhances On the other hand, HIF-1 has been proposed common in ageing and in neurodegenerative 2+ 2+ Ca entry and mitochondrial Ca content, as a neuroprotective factor, which has ability to diseases (Devos et al., 2020). Abnormal iron potentiates posttranscriptional trafficking of suppress neuronal cell death caused by hypoxia metabolism generates hydroxyl radicals 2+ L-type Ca channels. Both hypoxia and Aβ can or oxidative stress, and to protect against Aβ through the Fenton reaction, triggers oxidative trigger the activation of microglia, leading to peptide toxicity (Zheng et al., 2015; Ashok et stress reactions, causes lipid peroxidation a maladaptive neuroinflammatory response. al., 2017; Merelli et al., 2018). Recombinant and damages in cell protein and DNA, and Whilst, neuroinflammation itself could be adeno-associated virus vector expressing ultimately leads to cell death. Iron promotes another initiating pathological trigger of AD the human HIF-1α gene recombinant adeno- Aβ aggregation and induces aggregation of

310 ｜NEURAL REGENERATION RESEARCH｜Vol 16｜No.2｜February 2021 hyperphosphorylated tau. Iron-Aβ interaction Received: March 22, 2020 exhibits toxic effects through ROS. Iron Peer review started: April 9, 2020 chelators, such as desferoxamine, deferiprone, Accepted: May 6, 2020 deferasirox, have generated some promising Published online: August 24, 2020 results in both preclinical studies and some clinical trials for the AD treatment. However, https://doi.org/10.4103/1673-5374.290898 the potential role of HIF stabilization by these How to cite this article: Hassan H, Chen R (2021) agents has not been documented (Merelli Hypoxia in Alzheimer’s disease: effects of hypoxia et al., 2018). Iron chelators can cause iron inducible factors. Neural Regen Res 16(2):310-311. chelation and HIF activation simultaneously, as Copyright license agreement: The Copyright iron is one of the cofactors of HIF PHD (Figure License Agreement has been signed by both 1). M30, a multi-target iron chelator, has been authors before publication. reported to increase the HIF-1 protein level Plagiarism check: and to upregulate expression of the HIF-1 Checked twice by iThenticate. downstream genes, such as vascular endothelial Peer review: Externally peer reviewed. growth factor and erythropoietin. It has been Open access statement: This is an open access reported M30 simultaneously attenuates tau journal, and articles are distributed under the phosphorylation and protects cortical neurons terms of the Creative Commons Attribution- against Aβ25–35 toxicity (Merelli et al., 2018). NonCommercial-ShareAlike 4.0 License, which In a series of single blinded clinical trials, allows others to remix, tweak, and build upon the deferiprone is found to be feasible to treat work non-commercially, as long as appropriate the mild cognitive impairment of AD patients credit is given and the new creations are licensed (NCT02878538). Figure 1 ｜ Schematic diagram describing effects under the identical terms. of hypoxia and hypoxia mimetic agents on However, there was no evidence for the Open peer reviewer: Ivan Fernandez-Vega, neurons in Alzheimer’s disease (AD) process. Universidad de Oviedo, Spain. cognitive efficacy of two of metal protein Severe and/or chronic hypoxia can leads to Additional file:Open peer review report 1. attenuating compounds – clioquinol and PBT2, amyloid beta (Aβ) peptide formation and in AD patients (Sampson et al., 2014). Large aggregation, Ca2+ dyshomeostasis, reactive oxygen clinical trials are now requested to demonstrate species (ROS) formation in neurons as well as References cognitive efficacy of PBT2. neuroinflammation (Chen et al., 2018). While mild, moderate and/or intermittent hypoxia have been Ashok BS, Ajith TA, Sivanesan S (2017) Hypoxia-inducible A new generation of iron chelators with found to induce protective adaptations in the factors as neuroprotective agent in Alzheimer’s multifunction is needed for treating AD. brain (Lall et al., 2019). Hypoxia inducible factor disease. Clin Exp Pharmacol Physiol 44:327-334. Ideally, the new agents will have the capacity (HIF), a key mediator of oxygen homeostasis, Brookmeyer R, Abdalla N, Kawas CH, Corrada MM (2018) Forecasting the prevalence of preclinical and clinical to interfere with another signaling pathway in generates numerous pleiotropic protective effects, Alzheimer’s disease in the United States. Alzheimers addition to iron chelation, to stop or reverse but also participates in Aβ peptide formation Dement 14:121-129. the AD process. Iron chelators can lead to and aggregation. Hypoxia mimetic agents, Chen RL, Balami J, Esiri M, Chen LH, Buchan AM (2010) both iron chelation and HIF activation, but the both iron chelators and HIF prolyl hydroxylase Ischaemic stroke in the elderly: an overview of (PHD) inhibitors, can remove ROS and reduce latter is not well studied when treating the evidence. Nat Rev Neurol 6:256-265. neuroinflammation, in addition to activating Chen RL, Lai UH, Zhu LL, Singh A, Ahmed M, Forsyth NR neurodegenartive disease with iron chelators. HIF. Pharmacological stabilization of HIF can be (2018) Reactive Oxygen Species (ROS) formation in Activation of HIF can add an advantage for neuroprotective and be explored as an adjunctive the brain at different oxygen levels: role of hypoxia iron chelation therapy to activate endogenous therapy for AD. inducible factors. Front Cell Dev Biol 6:132. neuroregenerative pathways, in addition to Devos D, Cabantchik ZI, Moreau C, Danel V, Mahoney- inhibition of ROS production (Figure 1). Since Sanchez L, Bouchaoui H, Gouel F, Rolland AS, Pharmacological stabilization of HIF can be Duce JA, Devedjian JC; FAIRPARK-II and FAIRALS- the expression and function of PHDs have been neuroprotective and explored as an adjunctive II studygroups (2020) Conservative iron chelation shown to vary among tissues, the distinct role therapy for AD. Iron chelators have the potential for neurodegenerative diseases such as Parkinson’s of HIF alpha isoforms should be considered. to activate HIF in addition to iron chelation. The disease and amyotrophic lateral sclerosis. J Neural Attention need to be pay on the ability of neuroprotective effects of iron chelators are Transm (Vienna) 127:189-203. the novel iron chelators to induce different Lall R, Mohammed R, Ojha U (2019) What are the acting against the generation of free radicals links between hypoxia and Alzheimer’s disease? response of HIF-1α and HIF-2α. derived from iron, but could also be due to Neuropsychiatr Dis Treat 15:1343-1354. In conclusion, cerebral hypoxia is associated upregulation of the hypoxia rescue genes via Li X, Cui X, Chen Y, Chen T, Xu H, Yin H, Wu Y (2018) Therapeutic potential of a prolyl hydroxylase inhibitor with AD. The effects of hypoxia on the brain HIF stabilization (Merelli et al., 2018). The amount of HIF can be adjusted with doses of FG-4592 for Parkinson’s diseases in vitro and in vivo: depends on its duration and extent. Mild, regulation of redox biology and mitochondrial function. moderate and/or intermittent hypoxia can hypoxia mimetic agents, and the specific HIF-1 Front Aging Neurosci 10:121. be protective while severe and/or chronic or HIF-2 activation can be achievable (Chen et Merelli A, Rodríguez JCG, Folch J, Regueiro MR, Camins A, hypoxia is detrimental. Chronic hypoxia al., 2018). Carefully monitoring the HIF-1 and Lazarowski A (2018) Understanding the role of hypoxia inducible factor during for new not only promotes Aβ formation and HIF-2 activation by some novel iron chelators will help translate iron chelation therapy for therapeutics opportunities. Curr Neuropharmacol accumulation, but also aggravates Aβ toxicity 16:1484-1498. by increasing ROS and causing calcium neurodegenerative diseases, including the AD. Mijajlović MD, Pavlović A, Brainin M, Heiss WD, Quinn TJ, dyshomeostasis. Furthermore, both chronic The tissue specific HIF alpha isoform activation Ihle-Hansen HB, Hermann DM, Assayag EB, Richard E, hypoxia and Aβ activate microglia leading by iron chelators merits further investigation. Thiel A, Kliper E, Shin Y, Kim YH, Choi S, Jung S, Lee YB, Sinanović O, Levine DA, Schlesinger I, Mead G, et al. to a neuroinflammatory response, which The authors thank Prof. Christopher Exley, Keele (2017) Post-stroke dementia - a comprehensive review. has a detrimental role in AD pathogenesis. BMC Med 15:11. The restoration of normal oxygen tension University, UK, for critical comments. Rawlinson C, Jenkins SI, Thei L, Dallas ML, Chen RL (2020) in the brain would reduce or converse the Post-ischaemic immunological response in the brain: neurodegeneration. The molecules targeted This work was supported by a funding from targeting microglia in ischaemic stroke therapy. Brain Sci 10:159. by hypoxia can provide therapeutic strategies the Petroleum Technology Development Fund, Nigeria. Sampson EL, Jenagaratnam L, McShane R (2014) Metal and interventions against some common protein attenuating compounds for the treatment of neurodegenerative diseases, including * Alzheimer’s dementia. Cochrane Database Syst Rev the AD. HIF, an important physiological Halimatu Hassan, Ruoli Chen 2:CD005380. response mechanism to hypoxia, enhances School of Pharmacy and Bioengineering, Keele Zheng H, Fridkin M, Youdim M (2015) New approaches to University, Staffordshire, UK treating Alzheimer’s disease. Perspect Medicin Chem neuroprotective compensatory pathways 7:1-8. involved in many physiological processes. HIF *Correspondence to: Ruoli Chen, PhD, stabilization is not the same as hypoxia, and is [email protected]; [email protected]. P-Reviewer: Fernandez-Vega I; C-Editors: Zhao M, Li JY; only a part of hypoxia-induced changes in the https://orcid.org/0000-0001-8745-5902 T-Editor: Jia Y cells. (Ruoli Chen)

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