title: Bioenergetic mechanisms in astrocytes may contribute to amyloid plaque deposition and toxicity.
abstract: Alzheimer disease (AD) is characterized neuropathologically by synaptic disruption, neuronal loss, and deposition of amyloid β (Aβ) protein in brain structures that are critical for memory and cognition. There is increasing appreciation, however, that astrocytes, which are the major non-neuronal glial cells, may play an important role in AD pathogenesis. Unlike neurons, astrocytes are resistant to Aβ cytotoxicity, which may, in part, be related to their greater reliance on glycolytic metabolism. Here we show that, in cultures of human fetal astrocytes, pharmacological inhibition or molecular down-regulation of a main enzymatic regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB3), results in increased accumulation of Aβ within and around astrocytes and greater vulnerability of these cells to Aβ toxicity. We further investigated age-dependent changes in PFKFB3 and astrocytes in AD transgenic mice (TgCRND8) that overexpress human Aβ. Using a combination of Western blotting and immunohistochemistry, we identified an increase in glial fibrillary acidic protein expression in astrocytes that paralleled the escalation of the Aβ plaque burden in TgCRND8 mice in an age-dependent manner. Furthermore, PFKFB3 expression also demonstrated an increase in these mice, although at a later age (9 months) than GFAP and Aβ. Immunohistochemical staining showed significant reactive astrogliosis surrounding Aβ plaques with increased PFKFB3 activity in 12-month-old TgCRND8 mice, an age when AD pathology and behavioral deficits are fully manifested. These studies shed light on the unique bioenergetic mechanisms within astrocytes that may contribute to the development of AD pathology.
authors: From the Division of Neurology, Department of Medicine, Institute of Neuroscience and Mental Health, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors: Wen
authors: W
authors: Fu
authors: From the Division of Neurology, Department of Medicine, Institute of Neuroscience and Mental Health, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors: Diya
authors: D
authors: Shi
authors: From the Division of Neurology, Department of Medicine, Institute of Neuroscience and Mental Health, University of Alberta, Edmonton, Alberta T6G 2S2, Canada Department of Biochemistry, and.
authors: David
authors: D
authors: Westaway
authors: From the Division of Neurology, Department of Medicine, Institute of Neuroscience and Mental Health, University of Alberta, Edmonton, Alberta T6G 2S2, Canada jack.jhamandas@ualberta.ca.
authors: Jack H
authors: JH
authors: Jhamandas
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001522:Behavior, Animal; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; C528900:glial fibrillary astrocytic protein, mouse; C107345:PFKFB3 protein, human; C000595376:PFKFB3 protein, mouse; D025481:Phosphofructokinase-2
keywords: Alzheimer disease; amyloid precursor protein (APP); amyloid β (Aβ); astrocyte; glial cell; glycolysis; phosphofructokinase; reactive astrogliosis