title: An alkaline phosphatase transport mechanism in the pathogenesis of Alzheimer's disease and neurodegeneration.
abstract: Systemic inflammation is associated with loss of blood-brain barrier integrity and neuroinflammation that lead to the exacerbation of neurodegenerative diseases. It is also associated specifically with the characteristic amyloid-β and tau pathologies of Alzheimer's disease. We have previously proposed an immunosurveillance mechanism for epithelial barriers involving negative feedback-regulated alkaline phosphatase transcytosis as an acute phase anti-inflammatory response that hangs in the balance between the resolution and the progression of inflammation. We now extend this model to endothelial barriers, particularly the blood-brain barrier, and present a literature-supported mechanistic explanation for Alzheimer's disease pathology with this system at its foundation. In this mechanism, a switch in the role of alkaline phosphatase from its baseline duties to a stopgap anti-inflammatory function results in the loss of alkaline phosphatase from cell membranes into circulation, thereby decreasing blood-brain barrier integrity and functionality. This occurs with impairment of both amyloid-β efflux and tau dephosphorylating activity in the brain as alkaline phosphatase is replenished at the barrier by receptor-mediated transport. We suggest systemic alkaline phosphatase administration as a potential therapy for the resolution of inflammation and the prevention of Alzheimer's disease pathology as well as that of other inflammation-related neurodegenerative diseases.
authors.affiliation: AMRIF B.V., Agro Business Park 10, 6708PW Wageningen, The Netherlands. Electronic address: A.F.Pike@uu.nl.
authors.forename: Adrianne F
authors.initials: AF
authors.lastname: Pike
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80177, 3508TD Utrecht, The Netherlands.
authors.forename: Nynke I
authors.initials: NI
authors.lastname: Kramer
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80177, 3508TD Utrecht, The Netherlands.
authors.forename: Bas J
authors.initials: BJ
authors.lastname: Blaauboer
authors.affiliation: AMRIF B.V., Agro Business Park 10, 6708PW Wageningen, The Netherlands; Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80177, 3508TD Utrecht, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: Seinen
authors.affiliation: AMRIF B.V., Agro Business Park 10, 6708PW Wageningen, The Netherlands; Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80177, 3508TD Utrecht, The Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Brands
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology* / Q000517:prevention & control; D000818:Animals; D006801:Humans; D007249:Inflammation / Q000150:complications; D009928:Organ Specificity; D021381:Protein Transport
chemical_list: D000469:Alkaline Phosphatase
keywords: Alkaline phosphatase; Alzheimer’s disease; Blood-brain barrier; Neurodegenerative diseases; Neuroinflammation; RESCAP