An alkaline phosphatase transport mechanism in the pathogenesis of Alzheimer's disease and neurodegeneration.
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.
['Pike|Adrianne F|AF|', 'Kramer|Nynke I|NI|', 'Blaauboer|Bas J|BJ|', 'Seinen|Willem|W|', 'Brands|Ruud|R|']
D000469:Alkaline Phosphatase D000544:Alzheimer Disease D000818:Animals D006801:Humans D007249:Inflammation D009928:Organ Specificity D021381:Protein Transport
Alkaline phosphatase Blood-brain barrier Neuroinflammation Neurodegenerative diseases Alzheimer’s disease RESCAP