Immunoglobulin G Fc receptor deficiency prevents Alzheimer-like pathology and cognitive impairment in mice
| Autor: | Guadalupe Ortiz-Muñoz, Emilio Ambrosio, Osborne F. X. Almeida, Carmen Gomez-Guerrero, Paula Fernandez-Vizarra, Alejandro Higuera-Matas, Virginia Lopez-Parra, Oscar Lopez-Franco, Jesús Egido, Beñat Mallavia |
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| Rok vydání: | 2012 |
| Předmět: |
Apolipoprotein E
medicine.medical_specialty Pathology Amyloid Fc receptor Hippocampus Immunoglobulin G Mice Alzheimer Disease Internal medicine medicine Amyloid precursor protein Animals Receptor Mice Knockout Neurons biology Behavior Animal Receptors IgG medicine.disease Fragment crystallizable region Endocrinology Immunology biology.protein Neurology (clinical) Alzheimer's disease Cognition Disorders |
| Zdroj: | Brain : a journal of neurology. 135(Pt 9) |
| ISSN: | 1460-2156 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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