Dissecting the Binding Profile of PET Tracers to Corticobasal Degeneration Tau Fibrils.

Yang Zhou,Agneta Nordberg,Hans Ågren,Junhao Li

doi:10.1021/acschemneuro.1c00536

Abstract

Alzheimer’s disease and primary tauopathies are characterized by the presence of tau pathology in brain. Several tau positron emission tomography (PET) tracers have been developed and studied in Alzheimer’s disease (AD), but there is still a lack of 4R-tau specific tracers for non-AD tauopathies. We here present the first computational study on the binding profiles of four tau different PET tracers, PI2620, CBD2115, PM-PBB3, and MK6240, to corticobasal degeneration (CBD) tau. The in silico results showed different preferences for the various binding sites on the 4R fibril, and especially an entry site, a concave site, and a core site showed high binding affinity to these tracers. The core site and entry site both showed higher binding affinity than the surface sites, but the tracers were less likely to enter these sites. PI2620, CBD2115, and PM-PBB3 all showed higher binding affinities to CBD tau than the 3R/4R tracer MK6240. The same strategy has also been applied to AD tau fibrils, and significant differences in selectivity of binding sites were also observed. A higher binding affinity was observed for CBD2115 and PM-PBB3 to AD tau compared to PI2620. None of the studied tracers showed a selectivity for 4R compared to 3R/4R tau. This study clearly shows that identified binding sites from cryo-EM with low resolution can be further refined by metadynamics simulations in order to provide atomic resolution of the binding modes as well as of the thermodynamic properties.

Highlights

Several neurodegenerative disorders, named tauopathies, are characterized by tau protein aggregates in brain
The microtubebinding domain, enclosed either by three (3R) or four (4R) repeating subdomains, is folded to be β-sheet rich and is aggregated chain by chain in the formation of the tau fibrils.[5,6]. Components of such tau fibrils vary for different tauopathies, and while both 3R tau and 4R tau are present in Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE), only 4R tau is found in corticobasal degeneration (CBD), globular glial tauopathy (GGT), argyrophilic grain disease (AGD), and progressive nuclear palsy (PSP), and 3R in
In vitro binding data for CBD2115, PM-PBB3, PI2640, and MK6240 in postmortem cortical brain tissue from AD, PSP, or CBD subjects indicate differences in binding properties between the different tau tracers.17,34,39,40 [3H-]MK6240 has shown a 100 times higher affinity in AD brain tissue compared to both PSP and CBD brain tissue.[33 10] and 2 times lower Kd binding values in PSP and CBD tissues have been reported for [3H-]CBD2115 compared to [3H-]MK6240.34 The same authors, Lindberg et al, observed a 5 times lower Kd value for [3H-]CBD2115 in PSP compared to CBD brain tissues.[34]

Summary

Introduction

Several neurodegenerative disorders, named tauopathies, are characterized by tau protein aggregates in brain. There are, large histopathological differences between the tauopathies such as Alzheimer’s disease (AD) (neurofibrillary tangles) and primary tauopathies, such as progressive nuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), globular glial tauopathy (GGT), argyrophilic grain disease (AGD), and Pick’s disease (PiD).[1−4] Tau aggregation has been identified as filaments, which generate abnormal tau fibrils in brain. The microtubebinding domain, enclosed either by three (3R) or four (4R) repeating subdomains, is folded to be β-sheet rich and is aggregated chain by chain in the formation of the tau fibrils.[5,6] Components of such tau fibrils vary for different tauopathies, and while both 3R tau and 4R tau are present in AD and CTE, only 4R tau is found in CBD, GGT, AGD, and PSP, and 3R in. Recent studies indicate that the tau fibril varies in its folding pattern between different tauopathies,[7] indicating that each tauopathy is characterized by a disease-specific misfolding mode, e.g., AD-fold and CBD-fold (Figure 1).[8,9] The imaging of the different tau fibrils has become an important goal for early detection and differential diagnosis of various neurodegenerative diseases.[8,10−12]

Methods

Results

Conclusion