Abstract
In recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer’s disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related dementias, such as Pick’s disease, have not been widely explored. To design disease-specific and tau-selective PET tracers, it is important to determine where and how PET tracers bind to tau filaments. In this paper, we present the first molecular modelling study on PET probe binding to the structured core of tau filaments from a patient with Pick’s disease (TauPiD). We have used docking, molecular dynamics simulations, binding-affinity and tunnel calculations to explore TauPiD binding sites, binding modes, and binding energies of PET probes (AV-1451, MK-6240, PBB3, PM-PBB3, THK-5351 and PiB) with TauPiD. The probes bind to TauPiD at multiple surface binding sites as well as in a cavity binding site. The probes show unique surface binding patterns, and, out of them all, PM-PBB3 proves to bind the strongest. The findings suggest that our computational workflow of structural and dynamic details of the tau filaments has potential for the rational design of TauPiD specific PET tracers.
Highlights
Accepted: 27 December 2020Filamentous tau aggregates are the histopathological hallmark of a group of neurodegenerative diseases including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), and familial frontotemporal lobar degeneration with underlying tau pathology (FTLD-Tau) collectively referred as tauopathies [1]
[18 F]PM-PBB3 positron emission tomography (PET) imaging was demonstrated to be useful for the differential diagnosis of non-AD dementia patients (e.g., PSP, CBD, and Pick disease) [16]
Binding of other tracers to tau filaments derived from non-AD brains is still under investigation
Summary
Filamentous tau aggregates are the histopathological hallmark of a group of neurodegenerative diseases including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), and familial frontotemporal lobar degeneration with underlying tau pathology (FTLD-Tau) collectively referred as tauopathies [1]. Arranged either symmetrically base-to-base (PHF) or back-to-base (SF) The cores in both types of filament consist of 73 residues (V306–F378) with eight β-strands (β1–β8). A total of nine β-strands (β1–β9) is arranged in four cross-β packing stacks in TauPiD These cryo-EM studies raise the interesting question as to whether different tau filament structures can be distinguished by tau tracers, which have recently been developed for in vivo positron emission tomography (PET) imaging. The binding properties of these PET tracers with PHFs and SFs were examined by computational modeling using structural information from cryo-EM studies [25]. Since the binding specificity of current tau PET probes have not been completely validated against tau pathologies, approaches employing the structure-guided design of tracers for different filaments can be extremely useful. In order to elucidate the binding mechanism of PET probes in TauPiD , we performed computational modeling to characterize the binding of various PET probes to TauPiD , and obtained insights into their unique binding properties
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