title: Distinct Therapeutic Mechanisms of Tau Antibodies: Promoting Microglial Clearance Versus Blocking Neuronal Uptake.
abstract: Tauopathies are neurodegenerative diseases characterized by accumulation of Tau amyloids, and include Alzheimer disease and certain frontotemporal dementias. Trans-neuronal propagation of amyloid mediated by extracellular Tau may underlie disease progression. Consistent with this, active and passive vaccination studies in mouse models reduce pathology, although by unknown mechanisms. We previously reported that intracerebroventricular administration of three anti-Tau monoclonal antibodies (HJ8.5, HJ9.3, and HJ9.4) reduces pathology in a model overexpressing full-length mutant (P301S) human Tau. We now study effects of these three antibodies and a negative control antibody (HJ3.4) on Tau aggregate uptake into BV2 microglial-like cells and primary neurons. Antibody-independent Tau uptake into BV2 cells was blocked by heparin, consistent with a previously described role for heparan sulfate proteoglycans. Two therapeutic antibodies (HJ8.5 and HJ9.4) promoted uptake of full-length Tau fibrils into microglia via Fc receptors. Surprisingly, HJ9.3 promoted uptake of fibrils composed of the Tau repeat domain or Alzheimer disease-derived Tau aggregates, but failed to influence full-length recombinant Tau fibrils. Size fractionation of aggregates showed that antibodies preferentially promote uptake of larger oligomers (n ≥ ∼ 20-mer) versus smaller oligomers (n ∼ 10-mer) or monomer. No antibody inhibited uptake of full-length recombinant fibrils into primary neurons, but HJ9.3 blocked neuronal uptake of Tau repeat domain fibrils and Alzheimer disease-derived Tau. Antibodies thus have multiple potential mechanisms, including clearance via microglia and blockade of neuronal uptake. However these effects are epitope- and aggregate size-dependent. Establishing specific mechanisms of antibody activity in vitro may help in design and optimization of agents that are more effective in vivo.
authors.affiliation: From the Department of Neurology, Washington University in St. Louis, St. Louis, Missouri 63110 and.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Funk
authors.affiliation: the Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Hilda
authors.initials: H
authors.lastname: Mirbaha
authors.affiliation: From the Department of Neurology, Washington University in St. Louis, St. Louis, Missouri 63110 and.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: From the Department of Neurology, Washington University in St. Louis, St. Louis, Missouri 63110 and.
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.affiliation: the Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, Texas 75390 marc.diamond@utsouthwestern.edu.
authors.forename: Marc I
authors.initials: MI
authors.lastname: Diamond
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000682:Amyloid; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D002460:Cell Line; D002540:Cerebral Cortex / Q000473:pathology; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017452:Receptors, IgG / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000276:immunology*
chemical_list: D000682:Amyloid; D000906:Antibodies; C485701:Fcgr1 protein, mouse; D019812:Heparan Sulfate Proteoglycans; D017452:Receptors, IgG; D016875:tau Proteins
keywords: Tau protein (Tau); clearance; immunotherapy; microglia; neuron; tauopathy