Comparative In Vitro and In Vivo Quantifications of Pathologic Tau Deposits and Their Association with Neurodegeneration in Tauopathy Mouse Models

Abstract

Fibrillary tau aggregates in Alzheimer disease and allied neurodegenerative disorders have been visualized in vivo by PET, whereas mechanistic links between PET-detectable tau deposits and neurotoxicity remain elusive. Here, we took advantage of transgenic mouse models of tauopathies to evaluate associations between PET and postmortem measures of tau probe binding and their relation to neuronal loss. PET with a tau probe,C-PBB3 (2-((1E,3E)-4-(6-(C-methylamino)pyridine-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol), and volumetric MRI were performed for transgenic rTg4510 mice and nontransgenic mice. Binding of C-PBB3 and its blockade by another tau binding compound, AV-1451 (-(6-fluoropyridine-3-yl)-5H-pyrido[4,3-b]indole), in homogenized brains of tauopathy patients and rTg4510 and PS19 mice were quantified, andC-PBB3-positive and phosphorylated tau lesions in sectioned brains of these mice were assessed. In vivoC-PBB3 binding to the rTg4510 neocortex/hippocampus was increased relative to controls and correlated with local atrophy. In vitro C-PBB3 binding in the neocortex/hippocampus also correlated well with in vivo radioligand binding and regional atrophy in the same individual rTg4510 mice. By contrast, in vitroC-PBB3 binding was elevated in the brain stem but not hippocampus of PS19 mice, despite a pronounced loss of neurons in the hippocampus rather than brain stem. Finally, C-PBB3 and AV-1451 showed similar binding properties between mouse models and tauopathy patients. The present findings support the distinct utilities of C-PBB3 PET and MRI in rTg4510 and PS19 mice for quantitatively pursuing mechanisms connecting PET-detectable and PET-undetectable tau aggregations to neuronal death, which recapitulate 2 different modes of tau-provoked neurotoxicity.

In vivo binding of a tau imaging probe, [11C]PBB3, in patients with progressive supranuclear palsy

“…Our previous autoradiographic assays demonstrated only minimal nonspecific binding of [ 11 C]PBB3 in the basal ganglia sections . More recently, an in vitro binding assay using human brain homogenates has shown cross‐reactivity of [ 11 C]PBB3 with neither monoamine oxidase‐A nor MAO‐B . Another concern could be binding of [ 11 C]PBB3 to non‐tau protein fibrils, such as α‐synuclein aggregates .…”

“…18 More recently, an in vitro binding assay using human brain homogenates has shown cross-reactivity of [ 11 C]PBB3 with neither monoamine oxidase-A nor MAO-B. 38 Another concern could be binding of [ 11 C]PBB3 to non-tau protein fibrils, such as α-synuclein aggregates. 39 As a previous autoradiographic report documented, α-synuclein deposits with very high abundance in MSA brains could be captured by [ 11 C]PBB3, whereas none of the α-synuclein pathologies in dementia with Lewy bodies (DLB) brains were detectable by this radioligand.…”

Clinical heterogeneity of frontotemporal dementia and Parkinsonism linked to chromosome 17 caused by MAPT N279K mutation in relation to tau positron emission tomography features

“…In vivo offtarget binding and nonspecific retention of [ 11 C]PBB3 remain undetermined. Our recent in vitro binding assays using human brain homogenates have indicated that [ 11 C]PBB3 does not cross-react with monoamine oxidases A and B, 35 which is in clear distinction from properties of other tau radioligands, including [ 18 F]AV-1451 36 and [ 18 F]THK5351. 37 This observation, however, does not fully ensure the selectivity of [ 11 C]PBB3 for tau fibrils in PET imaging of living patients with tauopathies.…”

Tau deposition is associated with imaging patterns of tissue calcification in the P301L mouse model of human tauopathy

“…P301S and P301L lines (transgenic for a human 4 repeat tau isoform) [6,[52][53][54], which have become important tools to study the mechanisms of abnormal tau aggregation and deposition in FTD (4 repeat tau) [61] and AD (3 and 4 repeat tau) [25, 33,41]. In the P301L 4 (Thy 1.2, pR5 line) [11,18], P301L (CaMKIIa) [23,43,62] and P301L (tetO) [14] mouse models, tau deposits begin forming before 3 months-of-age in neurons in the entorhinal cortex, hippocampus and later in the cortex, and amygdala; with neuroinflammation and impaired memory functions in hippocampus-and amygdala-dependent tasks manifesting at a later stage [49,50,67]. Brain atrophy and white matter changes indicating neurodegeneration were reported in P301L (CaMKIIa) mouse line around 9 months-of-age [16,23,43,62], which was driven by factors additional to human tau overexpression.…”

“…In the P301L 4 (Thy 1.2, pR5 line) [11,18], P301L (CaMKIIa) [23,43,62] and P301L (tetO) [14] mouse models, tau deposits begin forming before 3 months-of-age in neurons in the entorhinal cortex, hippocampus and later in the cortex, and amygdala; with neuroinflammation and impaired memory functions in hippocampus-and amygdala-dependent tasks manifesting at a later stage [49,50,67]. Brain atrophy and white matter changes indicating neurodegeneration were reported in P301L (CaMKIIa) mouse line around 9 months-of-age [16,23,43,62], which was driven by factors additional to human tau overexpression. However, unlike in human patients with tauopathies, brain calcifications have not been reported in transgenic mouse models of human disease.…”