Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice

Abnormal accumulation of β-amyloid (Aβ) in Alzheimer's disease (AD) is associated with prominent brain inflammation. Whereas earlier studies concluded that this inflammation is detrimental, more recent animal data suggest that at least some inflammatory processes may be beneficial and promote Aβ clearance. Consistent with these observations, overproduction of transforming growth factor (TGF)-β1 resulted in a vigorous microglial activation that was accompanied by at least a 50% reduction in Aβ accumulation in human amyloid precursor protein (hAPP) transgenic mice. In a search for inflammatory mediators associated with this reduced pathology, we found that brain levels of C3, the central component of complement and a key inflammatory protein activated in AD, were markedly higher in hAPP/TGF-β1 mice than in hAPP mice. To assess the importance of complement in the pathogenesis of AD-like disease in mice, we inhibited C3 activation by expressing soluble complement receptor-related protein y (sCrry), a complement inhibitor, in the brains of hAPP mice. Aβ deposition was 2- to 3-fold higher in 1-year-old hAPP/sCrry mice than in age-matched hAPP mice and was accompanied by a prominent accumulation of degenerating neurons. These results indicate that complement activation products can protect against Aβ-induced neurotoxicity and may reduce the accumulation or promote the clearance of amyloid and degenerating neurons. These findings provide evidence for a role of complement and innate immune responses in AD-like disease in mice and support the concept that certain inflammatory defense mechanisms in the brain may be beneficial in neurodegenerative disease.

[1]  D. Coppola,et al.  Microglial Activation and β-Amyloid Deposit Reduction Caused by a Nitric Oxide-Releasing Nonsteroidal Anti-Inflammatory Drug in Amyloid Precursor Protein Plus Presenilin-1 Transgenic Mice , 2002, The Journal of Neuroscience.

[2]  C. Abraham Reactive astrocytes and α1-antichymotrypsin in Alzheimer’s disease ☆ ☆ Supported by the NIH and the Alzheimer’s Association. , 2001, Neurobiology of Aging.

[3]  O. Lindvall,et al.  Stereological assessment of vulnerability of immunocytochemically identified striatal and hippocampal neurons after global cerebral ischemia in rats , 2001, Brain Research.

[4]  Z. Fishelson,et al.  Complement and apoptosis. , 2001, Molecular immunology.

[5]  Virginia M. Y. Lee,et al.  Complement activation by neurofibrillary tangles in Alzheimer's disease , 2001, Neuroscience Letters.

[6]  L. Mucke,et al.  TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice , 2001, Nature Medicine.

[7]  John D Lambris,et al.  Structure and biology of complement protein C3, a connecting link between innate and acquired immunity , 2001, Immunological reviews.

[8]  C. Lemere,et al.  Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease. , 2001, The American journal of pathology.

[9]  Brian J. Bacskai,et al.  Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy , 2001, Nature Medicine.

[10]  E. Lavi,et al.  Cutting Edge: C3, a Key Component of Complement Activation, Is Not Required for the Development of Myelin Oligodendrocyte Glycoprotein Peptide-Induced Experimental Autoimmune Encephalomyelitis in Mice1 , 2001, The Journal of Immunology.

[11]  J. Hardy,et al.  Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease , 2000, Nature.

[12]  Ralph A. Nixon,et al.  Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease , 2000, Nature.

[13]  P. Gasque,et al.  Complement components of the innate immune system in health and disease in the CNS. , 2000, Immunopharmacology.

[14]  J. Lambris,et al.  Complement and innate immunity. , 2000, Immunopharmacology.

[15]  R. Motter,et al.  Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease , 2000, Nature Medicine.

[16]  M. Emmerling,et al.  The role of complement in Alzheimer's disease pathology. , 2000, Biochimica et biophysica acta.

[17]  Kang Hu,et al.  High-Level Neuronal Expression of Aβ1–42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation , 2000, The Journal of Neuroscience.

[18]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[19]  B. Palanca,et al.  A critical role for murine complement regulator crry in fetomaternal tolerance. , 2000, Science.

[20]  N. Davoust,et al.  Central nervous system-targeted expression of the complement inhibitor sCrry prevents experimental allergic encephalomyelitis. , 1999, Journal of immunology.

[21]  M. Svensson,et al.  Glial responses to synaptic damage and plasticity , 1999, Journal of neuroscience research.

[22]  N. Davoust,et al.  Complement anaphylatoxin receptors on neurons: new tricks for old receptors? , 1999, Trends in Neurosciences.

[23]  R. Motter,et al.  Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse , 1999, Nature.

[24]  D. Giulian Microglia and the immune pathology of Alzheimer disease. , 1999, American Journal of Human Genetics.

[25]  D. Selkoe,et al.  Translating cell biology into therapeutic advances in Alzheimer's disease , 1999, Nature.

[26]  D. Collier,et al.  Stereological estimation of the total number of neurons in the murine hippocampus using the optical disector , 1999, The Journal of comparative neurology.

[27]  Sarah Tomlin,et al.  Microtechnology: Laying it on thick , 1999, Nature.

[28]  R. Macdonald,et al.  Renal, central nervous system and pancreatic overexpression of recombinant soluble Crry in transgenic mice. A novel means of protection from complement-mediated injury. , 1999, Immunopharmacology.

[29]  P. Mcgeer,et al.  Inflammation of the brain in Alzheimer's disease: implications for therapy , 1999, Journal of leukocyte biology.

[30]  J. Alexander,et al.  Transgenic Mice Overexpressing the Complement Inhibitor Crry as a Soluble Protein Are Protected from Antibody-induced Glomerular Injury , 1998, The Journal of experimental medicine.

[31]  B. Bradt,et al.  Complement-dependent Proinflammatory Properties of the Alzheimer's Disease β-Peptide , 1998, Journal of Experimental Medicine.

[32]  Pier Paolo Pandolfi,et al.  Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies , 1998, Nature Genetics.

[33]  David Garrick,et al.  Repeat-induced gene silencing in mammals , 1998, Nature Genetics.

[34]  J. Rogers,et al.  Aggregation State‐Dependent Activation of the Classical Complement Pathway by the Amyloid β Peptide , 1997, Journal of neurochemistry.

[35]  R. Motter,et al.  Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease , 1997 .

[36]  A. Roher,et al.  Complement interactions with amyloid β1–42: A nidus for inflammation in AD brains , 1997 .

[37]  L. Lue,et al.  735 Molecular, immunohistochemical, and ultrastructural characterization of complement proteins, including C5b-9, in ALZHEIMER'S disease , 1996, Neurobiology of Aging.

[38]  Douglas Walker,et al.  Inflammation and Alzheimer's disease pathogenesis , 1996, Neurobiology of Aging.

[39]  M. Baudry,et al.  Hereditary Deficiencies in Complement C5 Are Associated with Intensified Neurodegenerative Responses That Implicate New Roles for the C-System in Neuronal and Astrocytic Functions , 1996, Neurobiology of Disease.

[40]  P. Anderson Clinical Immunology: Principles and Practice , 1996 .

[41]  A. Mccarthy Development , 1996, Current Opinion in Neurobiology.

[42]  L. Mucke,et al.  Synaptotrophic effects of human amyloid β protein precursors in the cortex of transgenic mice , 1994, Brain Research.

[43]  C. Cotman,et al.  beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain. , 1994, Journal of immunology.

[44]  P. Mcgeer,et al.  Complement activation by beta-amyloid in Alzheimer disease. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[45]  R. J. Mullen,et al.  NeuN, a neuronal specific nuclear protein in vertebrates. , 1992, Development.

[46]  G. Cole,et al.  Phagocytosis and deposition of vascular beta-amyloid in rat brains injected with Alzheimer beta-amyloid. , 1992, The American journal of pathology.

[47]  V. Holers,et al.  Distinct receptor and regulatory properties of recombinant mouse complement receptor 1 (CR1) and Crry, the two genetic homologues of human CR1 , 1992, The Journal of experimental medicine.