Biology subjects

Vogels, T.

Publications and source records attributed to Vogels, T..

3 recordsLinked to original sources

bioRxiv2024

Astrocytic tau inclusions lead to microglial abnormalities, but leave neuronal networks intact

Astrocytic tau inclusions are commonly found in the aging brain and primary tauopathies, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The functional consequences of these histopathological lesions, however, are unknown due to the lack of specific animal models. We have developed a mouse model of astrocytic tau pathology to study downstream effects on microglia and neuronal networks. We have designed an adeno-associated viral (AAV) vector expressing aggregation-prone human truncated tau (amino acids 151-391/4R) and red fluorophore mCherry in equal ratio under the astrocytic GFAP promotor. Injection of AAV-GFAP-htTau into the hippocampus of wild-type mice led to expression of human truncated tau in astrocytes and accumulation of soluble phosphorylated tau (p214, p231) but no detectable cognitive impairment. In vivo multiphoton imaging revealed alterations in microglial morphology in the vicinity of truncated tau positive astrocytes in the cortex. No alterations in firing patterns of excitatory cortical neurons surrounded by astrocytes overexpressing truncated tau were detected. These results suggest that early stages of astrocytic tau pathology lead to changes in microglial function, but not to functional impairment of neuronal networks.

neuroscience↗

bioRxiv2020

Bispecific tau antibodies with additional binding to C1q or alpha-synuclein

BackgroundAlzheimers 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 Parkinsons disease and Lewy body dementia also frequently occur together with tau pathology. 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. MethodsHerein, 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. ResultsThe 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. ConclusionBispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

neuroscience↗

bioRxiv2017

A neural model of working memory

Working memory, the ability to keep recently encountered information available for immediate processing, has been proposed to rely on two mechanisms that appear difficult to reconcile: selfsustained neural firing, or the opposite--activity-silent synaptic traces. Here we show that both phenomena can co-exist within a unified system in which neurons hold information in both activity and synapses. Rapid plasticity in flexibly-coding neurons allows features to be bound together into objects, with an important emergent property being the focus of attention. One memory item is held by persistent activity in an attended or \"focused\" state, and is thus remembered better than other items. Other, previously attended items can remain in memory but in the background, encoded in activity-silent synaptic traces. This dual functional architecture provides a unified common mechanism accounting for a diverse range of perplexing attention and memory effects that have been hitherto difficult to explain in a single theoretical framework.

neuroscience↗