title: Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is associated with deficiencies in cerebrovascular functions, e.g. reduced cerebral blood flow and capillary amyloid angiopathy, both of which are evident during the early phase of AD, thus local hypoxia/ischemia could augment the pathogenesis of AD. There is abundant literature revealing that exposures to hypoxia/ischemia increase the amyloidogenic processing of amyloid-β precursor protein (APP) leading to the accumulation of amyloid-β peptides in brain. This hypoxia-induced response has been attributed to a significant increase in the activities of β- and γ-secretases, whereas α-secretase activity decreases in hypoxia. Recent studies have indicated that hypoxia-inducible factor-1α (HIF-1α) stimulates the transcription of the β-secretase 1 (BACE1) gene through the hypoxia-response element in the BACE1 promoter. Moreover, HIF-1α protein can directly interact with the γ-secretase complex and increase its activity in a non-transcriptional manner. Hypoxia/ischemia also trigger endoplasmic reticulum stress and impair autophagy in brain, which consequently can stimulate the expression of presenilin 1 (PS1) and activate γ-secretase. Subsequently, PS1 protein can stabilize HIF-1α protein and in addition, APP intracellular domain peptide is able to induce the expression of HIF-1α. The activation of β- and γ-secretases is an evolutionarily conserved hypoxia response, e.g. it is also present in zebrafish. Given that β- and γ-secretases have many substrates in addition to APP, one could postulate that AD pathology is a byproduct of the rescue process mediated by these two aspartyl proteinases under hypoxic/ischemic conditions. We will review the recent evidence indicating that vascular dysfunctions can provoke AD pathology by activating β- and γ-secretases.
authors.affiliation: Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Antero
authors.initials: A
authors.lastname: Salminen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Kauppinen
authors.affiliation: Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.|Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000378:metabolism*; D014652:Vascular Diseases / Q000150:complications / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor
keywords: Alzheimer's disease; BACE1; HIF-1α; PS2V; hypoxia; ischemia; presenilin