Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease
Markus Britschgi,C. E. Olin,Hudson Johns,Yoshiko Takeda-Uchimura,Melburne C. Lemieux,Kaspar Rufibach,Jayakumar Rajadas,Hua Zhang,Beren H. Tomooka,William H. Robinson,William H. Robinson,C. Clark,Anne M. Fagan,Douglas Galasko,David M. Holtzman,Marek Jutel,J. A. Kaye,Cynthia A. Lemere,Jerzy Leszek,Guangpu Li,Elaine R. Peskind,Joseph F. Quinn,Jerome A. Yesavage,Jerome A. Yesavage,Jorge Ghiso,Tony Wyss-Coray,Tony Wyss-Coray +26 more
TLDR
The findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides and stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.Abstract:
A number of distinct β-amyloid (Aβ) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Aβ-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 Aβ and amyloidogenic non-Aβ 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 Aβ and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Aβ1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Aβ, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Aβ toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Aβ the monkeys developed high titers not only against Aβ 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 Aβ 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.read more
Citations
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Journal ArticleDOI
Cerebrospinal fluid and plasma biomarkers in Alzheimer disease.
TL;DR: The rationales behind and the diagnostic performances of the core cerebrospinal fluid biomarkers for AD, namely total tau, phosphorylated tau and the 42 amino acid form of amyloid-β are presented.
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Immune Activation in Brain Aging and Neurodegeneration: Too Much or Too Little?
TL;DR: The consequences of gain versus loss of function with an emphasis on microglia as sensors and effectors of immune function in the brain are explored, and the potential role of the peripheral environment in neurodegenerative diseases is discussed.
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Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β
Bernd Bohrmann,Karlheinz Baumann,Jörg Benz,Francoise Gerber,Walter Huber,Frédéric Knoflach,Jürg Messer,Krisztina Oroszlan,Robert Rauchenberger,Wolfgang F. Richter,Christine Rothe,Margit Urban,Michael Bardroff,Michael Winter,Christer Nordstedt,Hansruedi Loetscher +15 more
TL;DR: It is demonstrated that gantenerumab preferentially interacts with aggregated Aβ in the brain and lowers amyloid-β by eliciting effector cell-mediated clearance.
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Can Alzheimer disease be prevented by amyloid-beta immunotherapy?
TL;DR: Biomarkers for AD and imaging technology have improved greatly over the past 10 years and, in the future, might be used to identify presymptomatic, at-risk individuals who might benefit from Aβ immunization.
Journal ArticleDOI
Truncated and modified amyloid-beta species
TL;DR: Alzheimer’s disease pathology is closely connected to the processing of the amyloid precursor protein (APP) resulting in the formation of a variety of amyloids-beta (Aβ) peptides, which generate a plethora of peptides with different physiological and pathological properties that may modulate disease progression.
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