title: Hypoxia-inducible factors as neuroprotective agent in Alzheimer's disease.
abstract: Beta amyloid (Aβ)-42 peptide and phosphorylated tau protein have been demonstrated as the pathological hallmarks of Alzheimer's disease (AD). A gradual decline of oxygen and glucose supply to the brain during aging or hypoxia was manifested as a contributing factor to hypometabolism. The brain regions susceptible to hypometabolism are the hippocampus, entorhinal cortex and cognition-associated neocortical regions like parietal, temporal and frontal cortex. In AD patients, the brain regions with hypometabolism can trigger overexpression of amyloid precursor protein and decrease the clearance of Aβ. Aβ and hypoxia can evoke inflammation, oxidative stress and finally neuronal cell death. Among the transcription factors involved in the compensatory mechanism, hypoxia-inducible factor-1 alpha (HIF-1α) has a major role in the cellular adaptation by inducing the expression of several proteins, including vascular endothelial growth factor, erythropoietin and inducible nitric oxide synthase. Therefore, maintaining the HIF-1α level by inhibiting the prolyl 4-hydroxylase was effective to attenuate the nerve damage during hypoxia and postpone the incidence of AD. Agents such as iron chelators, and heavy metals like cobalt and nickel were demonstrated to be effective in maintaining the HIF-1α level in the nerve. This review article discusses the possible role of HIF-1α as a neuroprotector in AD and the future perspectives.
authors.affiliation: Department of Biochemistry, Sri Ramachandra Medical College and Research Institute, Sri Ramachandra University, Chennai, Tamil Nadu, India.
authors.forename: Ben Sundra
authors.initials: BS
authors.lastname: Ashok
authors.affiliation: Department of Biochemistry, Amala Institute of Medical Sciences, Thrissur, Kerala, India.
authors.forename: Thekkuttuparambil Ananthanarayanan
authors.initials: TA
authors.lastname: Ajith
authors.affiliation: Department of Research, Saveetha University, Chennai, Tamil Nadu, India.
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Sivanesan
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D055808:Drug Discovery; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; angiogenesis; beta amyloid; erythropoiesis; hypoxia; hypoxia-inducible factors; neurofibrillary tangles; oxidative stress; vascular endothelial growth factor