title: Immunoglobulin G Fc receptor deficiency prevents Alzheimer-like pathology and cognitive impairment in mice.
abstract: Alzheimer's disease is a severely debilitating disease of high and growing proportions. Hypercholesterolaemia is a key risk factor in sporadic Alzheimer's disease that links metabolic disorders (diabetes, obesity and atherosclerosis) with this pathology. Hypercholesterolaemia is associated with increased levels of immunoglobulin G against oxidized lipoproteins. Patients with Alzheimer's disease produce autoantibodies against non-brain antigens and specific receptors for the constant Fc region of immunoglobulin G have been found in vulnerable neuronal subpopulations. Here, we focused on the potential role of Fc receptors as pathological players driving hypercholesterolaemia to Alzheimer's disease. In a well-established model of hypercholesterolaemia, the apolipoprotein E knockout mouse, we report increased brain levels of immunoglobulin G and upregulation of activating Fc receptors, predominantly of type IV, in neurons susceptible to amyloid β accumulation. In these mice, gene deletion of γ-chain, the common subunit of activating Fc receptors, prevents learning and memory impairments without influencing cholesterolaemia and brain and serum immunoglobulin G levels. These cognition-protective effects were associated with a reduction in synapse loss, tau hyperphosphorylation and intracellular amyloid β accumulation both in cortical and hippocampal pyramidal neurons. In vitro, activating Fc receptor engagement caused synapse loss, tau hyperphosphorylation and amyloid β deposition in primary neurons by a mechanism involving mitogen-activated protein kinases and β-site amyloid precursor protein cleaving enzyme 1. Our results represent the first demonstration that immunoglobulin G Fc receptors contribute to the development of hypercholesterolaemia-associated features of Alzheimer's disease and suggest a new potential target for slowing or preventing Alzheimer's disease in hypercholesterolaemic patients.
authors.affiliation: Renal and Vascular Inflammation, Nephrology Department, IIS-Fundacion Jimenez Diaz, Autonoma University, Avda. Reyes Catolicos 2, 28040 Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Fernandez-Vizarra
authors.forename: Oscar
authors.initials: O
authors.lastname: Lopez-Franco
authors.forename: Beñat
authors.initials: B
authors.lastname: Mallavia
authors.forename: Alejandro
authors.initials: A
authors.lastname: Higuera-Matas
authors.forename: Virginia
authors.initials: V
authors.lastname: Lopez-Parra
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Ortiz-Muñoz
authors.forename: Emilio
authors.initials: E
authors.lastname: Ambrosio
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.forename: Osborne F X
authors.initials: OF
authors.lastname: Almeida
authors.forename: Carmen
authors.initials: C
authors.lastname: Gomez-Guerrero
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism
chemical_list: C485701:Fcgr1 protein, mouse; D017452:Receptors, IgG