Oligomeric tau-targeted immunotherapy in Tg4510 mice

Abstract

BackgroundFinding ways to reverse or prevent the consequences of pathogenic tau in the brain is of considerable importance for treatment of Alzheimer’s disease and other tauopathies. Immunotherapy against tau has shown promise in several mouse models. In particular, an antibody with selectivity for oligomeric forms of tau, tau oligomer monoclonal antibody (TOMA), has shown rescue of the behavioral phenotype in several murine models of tau deposition.MethodsIn this study, we examined the capacity of TOMA to rescue the behavioral, histological, and neurochemical consequences of tau deposition in the aggressive Tg4510 model. We treated mice biweekly with 60 μg TOMA i.p. from 3.5 to 8 months of age.ResultsNear the end of the treatment, we found that oligomeric tau was elevated in both the CSF and in plasma. Further, we could detect mouse IgG in Tg4510 mouse brain after TOMA treatment, but not after injection with mouse IgG1 as control. However, we did not find significant reductions in behavioral deficits or tau deposits by either histological or biochemical measurements.ConclusionsThese data suggest that there is some exposure of the Tg4510 mouse brain to TOMA, but it was inadequate to affect the phenotype in these mice at the doses used. These data are consistent with other observations that the rapidly depositing Tg4510 mouse is a challenging model in which to demonstrate efficacy of tau-lowering treatments compared to some other preclinical models of tau deposition/overexpression.

Conformation-selective tau monoclonal antibodies inhibit tau pathology in primary neurons and a mouse model of Alzheimer’s disease

“…DMR7 and SKT82 were administered at a dose of 60 mg/kg by i.p. injection in this study which is consistent with previous studies [ 28 , 41 ], although other tau mAbs have been tested at doses as low as 10 mg/kg [ 43 ].…”

“…In contrast, SKT82 and DMR7 were developed against human AD brain-derived insoluble tau extracts in order to target pathological tau species present in human disease. Passive immunotherapy studies with the conformation-selective MC1 antibody have demonstrated a reduction in hyperphosphorylated tau pathology but, like most tau mAb efficacy studies, these were evaluated in mouse models with overexpression of mutant human tau [ 36 , 40 , 41 , 43 ], whereas DMR7 and SKT82 were evaluated in the context of physiological endogenous mouse tau with AD-tau seeded pathology. DMR7 and SKT82 were administered at a dose of 60 mg/kg by i.p.…”

“…Several tau antibodies have been evaluated in preclinical models of AD, and these antibodies have targeted linear epitopes in the tau N-terminus [ 25 – 29 ], central domain [ 30 ], MTBRs [ 31 , 32 ] or specific phosphorylation sites such as pThr231 [ 33 ], pSer396 [ 33 , 34 ], pSer396/pSer404 [ 35 , 36 ], pSer404 [ 37 ], pSer413 [ 34 ], or pSer422 [ 38 ]. A few antibodies reported to selectively bind pathological tau oligomers [ 39 – 41 ] have also been evaluated in vivo in addition to the conformation-selective antibody MC1 [ 36 , 42 , 43 ]. A handful of passive and active tau immunotherapy approaches have progressed into phase I and phase II clinical trials, as reviewed elsewhere [ 44 ].…”

Brain cellular senescence in mouse models of Alzheimer’s disease

“…It is widely accepted that soluble aggregated oligomeric forms of tau or amyloid-beta (Aβ), as opposed to large aggregates such as neurofibrillary tangles and Aβ plaques, are the major pathogenic toxic species in AD and primary tauopathies [31,32]. Because of the enforced expression of their precursors (monomeric tau and amyloid precursor protein (APP)) as transgenes, soluble oligomeric forms of tau or Aβ appear early in the postnatal period or early adulthood (~ 4-12 weeks of age) in rodent models of Alzheimer's disease [33][34][35], before age-associated changes such as cellular senescence are present. It is thus unlikely that activation of aging-associated cellular senescence precedes the increase in soluble aggregated forms of tau or Aβ in rodent models of AD.…”

The tau oligomer antibody APNmAb005 detects early-stage pathological tau enriched at synapses and rescues neuronal loss in long-term treatments

“…In rTG4510 mice, which have more aggressive pathologies than JNPL3, TOMA did not affect tangle or tau monomer levels. It failed to rescue neuronal death in the hippocampus and behavioral deficits, but only managed to promoted the clearance of tau oligomers into the cerebrospinal fluid and blood serum ( 86 ). In comparison, APNmAb005 treatment promoted neuronal survival in the hippocampus of rTg4510 mice, accompanied by increases in total tau, pTau, synaptophysin, and esoTau levels ( Fig.…”