Bispecific Tau Antibodies with Additional Binding to C1q or Alpha-Synuclein.

BACKGROUND: Alzheimer's disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson's disease and Lewy body dementia also frequently occur together with tau pathology. OBJECTIVE: Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway. METHODS: Herein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q. RESULTS: Affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway. CONCLUSION: Bispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

Viral Delivery of Non-Mutated Human Truncated Tau to Neurons Recapitulates Key Features of Human Tauopathy in Wild-Type Mice.

BACKGROUND: Neuronal accumulation of hyperphosphorylated and truncated tau aggregates is one of the major defining factors and key drivers of neurodegeneration in Alzheimer's disease and other tauopathies. OBJECTIVE: We developed an AAV-induced model of tauopathy mediated by human truncated tau protein without familial frontotemporal dementia-related mutations to study tau propagation and the functional consequences of tau pathology. METHODS: We performed targeted transductions of the hippocampus or entorhinal cortex in adult mice followed by histological analysis to study the progression of hippocampal tau pathology and tau spreading. We performed behavioral analysis of mice with AAV-induced hippocampal tau pathology. RESULTS: AAV-induced hippocampal tau pathology was characterized by tau hyperphosphorylation (AT8 positivity), sarkosyl insolubility, and the presence of neurofibrillary tangles. AAV-induced tau pathology was associated with microgliosis and hypertrophic astrocytes in the absence of cognitive deficits. Additionally, the co-expression of mCherry fluorescent protein and human truncated tau enabled us to detect both local spreading of human tau and spreading from the entorhinal cortex to the synaptically connected dentate gyrus. CONCLUSION: Targeted delivery of AAV with truncated tau protein into subcortical and cortical structures of mammalian brains represents an efficient approach for creating temporally and spatially well-defined tau pathology suitable for in vivo studies of tau propagation and neuronal circuit deficits in Alzheimer's disease.