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Immunoglobulin G Fc receptor deficiency prevents Alzheimer-like pathology and cognitive impairment in mice

Paula Fernandez-Vizarra, Oscar Lopez-Franco, Beñat Mallavia, Alejandro Higuera-Matas, Virginia Lopez-Parra, Guadalupe Ortiz-Muñoz, Emilio Ambrosio, Jesus Egido, Osborne F. X. Almeida, Carmen Gomez-Guerrero
DOI: http://dx.doi.org/10.1093/brain/aws195 2826-2837 First published online: 8 September 2012

Summary

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.

  • Alzheimer’s disease
  • hypercholesterolaemia
  • apolipoprotein E
  • immunoglobulin receptors
  • cognitive dysfunction
  • Abbreviations
    apoE
    apolipoprotein E
    BACE1
    β-site amyloid precursor protein cleaving enzyme 1
    JNK
    c-Jun N-terminal kinase
    DKO
    double knockout
    ERK
    extracellular regulated mitogen-activated protein kinase
    GFAP
    glial fibrillary acidic protein
    IgG
    immunoglobulin G
    MCP1
    monocyte chemoattractant protein 1
    FcγR
    receptor for the constant Fc region of immunoglobulin G
    TNFα
    tumour necrosis factor α
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