A number of distinct -amyloid (A) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural A-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic A and amyloidogenic non-A species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of A and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of A1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant A, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from A toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with A the monkeys developed high titers not only against A peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of A antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD. A lzheimer's disease (AD) is the most common cause of dementia, affecting an estimated 5.3 million individuals in the United States alone. Deposits of -amyloid peptide (A) in extracellular plaques characterize the AD brain, but soluble oligomeric A species appear to be more neurotoxic than plaques and interfere with synaptic function (reviewed in ref. 1). Notably, most A peptides isolated from AD brains are posttranslationally modified and truncated (2-6), and some are proposed to be oxidized (7,8) or cross-linked at Tyr-10 (9). Although the pathogenic consequences of these modifications need to be resolved, most of them can stabilize A assemblies, interfere with proteolytic degradation, and increase A toxicity in vitro (7,8,10).One line of defense against toxic A species could be neutralizing antibodies. Stimulating the production of A antibodies by active immunization with synthetic A (11) or administering monoclonal A antibodies (12, 13) reduced amyloid pathology and inflammation and improved cognitive function in mouse models of AD (14). In patients with mild to moderate AD active immunization appears to reduce plaque load (15), and in some patients production of A antibodies correlated with attenuated cognitive decline (16). It has also been suggested that antibodies recognizing different domains (12,13,17) or conformations (18, 19) of A may have different efficacy in humans.Interestingly, antibodies agai...
BackgroundThe neuronal microtubule-associated protein tau becomes hyperphosphorylated and forms aggregates in tauopathies but the processes leading to this pathological hallmark are not understood. Because tauopathies are accompanied by neuroinflammation and the complement cascade forms a key innate immune pathway, we asked whether the complement system has a role in the development of tau pathology.FindingsWe tested this hypothesis in two mouse models, which expressed either a central inhibitor of complement or lacked an inhibitor of the terminal complement pathway. Complement receptor-related gene/protein y is the natural inhibitor of the central complement component C3 in rodents. Expressing a soluble variant (sCrry) reduced the number of phospho-tau (AT8 epitope) positive neurons in the brain stem, cerebellum, cortex, and hippocampus of aged P301L mutant tau/sCrry double-transgenic mice compared with tau single-transgenic littermates (JNPL3 line). CD59a is the major inhibitor of formation of the membrane attack complex in mice. Intrahippocampal injection of adeno-associated virus encoding mutant human P301L tau into Cd59a−/− mice resulted in increased numbers of AT8-positive cells compared with wild-type controls. This was accompanied by neuronal and synaptic loss and reduced dendritic integrity.ConclusionsOur data in two independent mouse models with genetic changes in key regulators of the complement system support the hypothesis that the terminal pathway has an active role in the development of tau pathology. We propose that inhibition of the terminal pathway may be beneficial in tauopathies.
BackgroundBiological pathways that significantly contribute to sporadic Alzheimer’s disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.ResultsTo access this information we probed relative levels of close to 600 secreted signaling proteins from patients’ blood samples using antibody microarrays and mapped disease-specific molecular networks. Using these networks as seeds we then employed independent genome and transcriptome data sets to corroborate potential pathogenic pathways.ConclusionsWe identified Growth-Differentiation Factor (GDF) signaling as a novel Alzheimer’s disease-relevant pathway supported by in vivo and in vitro follow-up experiments, demonstrating the existence of a highly informative link between cellular pathology and changes in circulatory signaling proteins.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0095-2) contains supplementary material, which is available to authorized users.
The growing link between systemic environment and brain function opens the possibility that cellular communication and composition in blood are correlated with brain health. We tested this concept in frontotemporal dementia with novel, unbiased tools that measure hundreds of soluble signaling proteins or characterize the vast immune cell repertoire in blood. With these tools we discovered complementary abnormalities indicative of abnormal T cell populations and autoimmunity in frontotemporal dementia.
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