title: Deglycosylated anti-amyloid beta antibodies reduce microglial phagocytosis and cytokine production while retaining the capacity to induce amyloid beta sequestration.
abstract: Accumulation of amyloid beta (Abeta) is a pathological hallmark of Alzheimer's disease, and lowering Abeta is a promising therapeutic approach. Intact anti-Abeta antibodies reduce brain Abeta through two pathways: enhanced microglial phagocytosis and Abeta transfer from the brain to the periphery (Abeta sequestration). While activation of microglia, which is essential for microglial phagocytosis, is necessarily accompanied by undesired neuroinflammatory events, the capacity for sequestration does not seem to be linked to such effects. We and other groups have found that simple Abeta binding agents are sufficient to reduce brain Abeta through the sequestration pathway. In this study, we aimed to eliminate potentially deleterious immune activation from antibodies without affecting the ability to induce sequestration. The glycan portion of immunoglobulin is critically involved in interactions with immune effectors including the Fc receptor and complement c1q; deglycosylation eliminates these interactions, while antigen (Abeta)-binding affinity is maintained. In this study, we investigated whether deglycosylated anti-Abeta antibodies reduce microglial phagocytosis and neuroinflammation without altering the capacity to induce Abeta sequestration. Deglycosylated antibodies maintained Abeta binding affinity. Deglycosylated antibodies did not enhance Abeta phagocytosis or cytokine release in primary cultured microglia, whereas intact antibodies did so significantly. Intravenous injection of deglycosylated antibodies elevated plasma Abeta levels and induced Abeta sequestration to a similar or greater degree compared with intact antibodies in an Alzheimer's transgenic mouse model without or with Abeta plaque pathology. We conclude that deglycosylated antibodies effectively induced Abeta sequestration without provoking neuroinflammation; thus, these deglycosylated antibodies may be optimal for sequestration therapy for Alzheimer's disease.
authors.affiliation: Department of Neurobiology, Kyoto Pharmaceutical University and 21st Century COE Program, Kyoto 607-8414, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Takata
authors.forename: Chiho
authors.initials: C
authors.lastname: Hirata-Fukae
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Becker
authors.forename: Saori
authors.initials: S
authors.lastname: Chishiro
authors.forename: Audrey J
authors.initials: AJ
authors.lastname: Gray
authors.forename: Kouhei
authors.initials: K
authors.lastname: Nishitomi
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Franz
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Kato
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Frank M
authors.initials: FM
authors.lastname: Laferla
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Matsuoka
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004660:Encephalitis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control; D005911:Gliosis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control; D006031:Glycosylation; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects* / Q000276:immunology; D011134:Polysaccharides / Q000737:chemistry / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D016207:Cytokines; D011134:Polysaccharides