Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy

Abstract

Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer’s disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants—WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick’s disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.

Tau-Mediated Dysregulation of Neuroplasticity and Glial Plasticity

“…Consistent with reports from other laboratories (Ramsden et al, 2005 ; Schindowski et al, 2006 ), we observed that mice with accelerated NFT deposits also developed rapid memory impairment (Koller et al, 2019 ). While our results were consistent with human data (reviewed in Nelson et al, 2012 ), other preclinical studies have shown that tau conformers, independent of NFT, underlie memory deficits and network alterations (Santacruz et al, 2005 ; Bolós et al, 2017 ; Green et al, 2019 ).…”

“…Gliosis closely follows the development of tauopathy in transgenic mouse models (Ramsden et al, 2005 ; Schindowski et al, 2006 ; Yoshiyama et al, 2007 ; de Calignon et al, 2012 ; Maeda et al, 2016 ). We developed several mouse models of tauopathy in our lab to understand how gliosis is differentially regulated in the presence of intracellular phosphorylated tau and NFT inclusions (Koller et al, 2019 ). These models express different human mutant tau constructs following neonatal delivery of recombinant adeno-associated viruses (AAV).…”

An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline

“…Using a panel of FTD-associated tau mutants, HDAC6 showed increased binding to P301L and S320F mutations. The exact properties of these particular mutants that enable more robust engagement with HDAC6 is not clear, however a recent study indicated synergistic aggregation and seeding of the P301L and S320F mutations [59][60][61] . Our data suggest that HDAC6 may preferentially target specific aggregate-prone conformations, or strains, via a chaperone bridge, as mutations that abrogate tau-chaperone binding also diminished tau-HDAC6 binding (Fig.…”

Photodynamic studies reveal rapid formation and appreciable turnover of tau inclusions

“…The tau inclusions that form are insoluble, Thioflavin S positive, and show fibrillar structure by electron microscopy (EM) [ 10 ]. Notably, BSCs are highly predictive of results obtained upon transgenic or rAAV-mediated expression of tau in rodent models [ 35 ].…”