Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3ß) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation.

It has been suggested that aberrant activation of glycogen synthase kinase-3-beta (GSK-3ß) can trigger abnormal tau hyperphosphorylation and aggregation, which ultimately leads to neuronal/synaptic damage and impaired cognition in Alzheimer disease (AD). We examined if isoform-selective partial reduction of GSK-3ß can decrease pathological tau changes, including hyperphosphorylation, aggregation, and spreading, in mice with localized human wild-type tau (hTau) expression in the brain. We used adeno-associated viruses (AAVs) to express hTau locally in the entorhinal cortex of wild-type and GSK-3ß hemi-knockout (GSK-3ß-HK) mice. GSK-3ß-HK mice had significantly less accumulation of hyperphosphorylated tau in synapses and showed a significant decrease of tau protein spread between neurons. In primary neuronal cultures from GSK-3ß-HK mice, the aggregation of exogenous FTD-mutant tau was also significantly reduced. These results show that a partial decrease of GSK-3ß significantly represses tau-initiated neurodegenerative changes in the brain, and therefore is a promising therapeutic target for AD and other tauopathies.

[18F]-AV-1451 binding profile in chronic traumatic encephalopathy: a postmortem case series.

INTRODUCTION: Chronic traumatic encephalopathy (CTE) is a tauopathy associated to repetitive head trauma. There are no validated in vivo biomarkers of CTE and a definite diagnosis can only be made at autopsy. Recent studies have shown that positron emission tomography (PET) tracer AV-1451 (Flortaucipir) exhibits high binding affinity for paired helical filament (PHF)-tau aggregates in Alzheimer (AD) brains but relatively low affinity for tau lesions in other tauopathies like temporal lobal degeneration (FTLD)-tau, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Little is known, however, about the binding profile of this ligand to the tau-containing lesions of CTE. OBJECTIVE: To study the binding properties of [18F]-AV-1451 on pathologically confirmed CTE postmortem brain tissue samples. METHODS: We performed [18F]-AV-1451 phosphor screen and high resolution autoradiography, quantitative tau measurements by immunohistochemistry and Western blot and tau seeding activity assays in brain blocks containing hippocampus, superior temporal cortex, superior frontal cortex, inferior parietal cortex and occipital cortex from 5 cases of CTE, across the stages of disease: stage II-III (n = 1), stage III (n = 3), and stage IV (n = 1). Importantly, low or no concomitant classic AD pathology was present in these brains. RESULTS: Despite the presence of abundant tau aggregates in multiple regions in all CTE brains, only faint or no [18F]-AV-1451 binding signal could be detected by autoradiography. The only exception was the presence of a strong signal confined to the region of the choroid plexus and the meninges in two of the five cases. Tau immunostaining and Thioflavin-S staining ruled out the presence of tau aggregates in those regions. High resolution nuclear emulsion autoradiography revealed the presence of leptomeningeal melanocytes as the histologic source of this off-target binding. Levels of abnormally hyperphosphorylated tau species, as detected by Western Blotting, and tau seeding activity were both found to be lower in extracts from cases CTE when compared to AD. CONCLUSION: AV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in CTE. The existence of disease-specific tau conformations may likely explain the differential binding affinity of this tracer for tau lesions in different tauopathies.

Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson's case.

[F-18]-AV-1451 is a novel positron emission tomography (PET) tracer with high affinity to neurofibrillary tau pathology in Alzheimer's disease (AD). PET studies have shown increased tracer retention in patients clinically diagnosed with dementia of AD type and mild cognitive impairment in regions that are known to contain tau lesions. In vivo uptake has also consistently been observed in midbrain, basal ganglia and choroid plexus in elderly individuals regardless of their clinical diagnosis, including clinically normal whose brains are not expected to harbor tau pathology in those areas. We and others have shown that [F-18]-AV-1451 exhibits off-target binding to neuromelanin, melanin and blood products on postmortem material; and this is important for the correct interpretation of PET images. In the present study, we further investigated [F-18]-AV-1451 off-target binding in the first autopsy-confirmed Parkinson's disease (PD) subject who underwent antemortem PET imaging. The PET scan showed elevated [F-18]-AV-1451 retention predominantly in inferior temporal cortex, basal ganglia, midbrain and choroid plexus. Neuropathologic examination confirmed the PD diagnosis. Phosphor screen and high resolution autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined with the exception of neuromelanin-containing neurons in the substantia nigra, leptomeningeal melanocytes adjacent to ventricles and midbrain, and microhemorrhages in the occipital cortex (all reflecting off-target binding), in addition to incidental age-related neurofibrillary tangles in the entorhinal cortex. Additional legacy postmortem brain samples containing basal ganglia, choroid plexus, and parenchymal hemorrhages from 20 subjects with various neuropathologic diagnoses were also included in the autoradiography experiments to better understand what [F-18]-AV-1451 in vivo positivity in those regions means. No detectable [F-18]-AV-1451 autoradiographic binding was present in the basal ganglia of the PD case or any of the other subjects. Off-target binding in postmortem choroid plexus samples was only observed in subjects harboring leptomeningeal melanocytes within the choroidal stroma. Off-target binding to parenchymal hemorrhages was noticed in postmortem material from subjects with cerebral amyloid angiopathy. The imaging-postmortem correlation analysis in this PD case reinforces the notion that [F-18]-AV-1451 has strong affinity for neurofibrillary tau pathology but also exhibits off-target binding to neuromelanin, melanin and blood components. The robust off-target in vivo retention in basal ganglia and choroid plexus, in the absence of tau deposits, meningeal melanocytes or any other identifiable binding substrate by autoradiography in the PD case reported here, also suggests that the PET signal in those regions may be influenced, at least in part, by biological or technical factors that occur in vivo and are not captured by autoradiography.

[F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging.

[F-18]-AV-1451, a PET tracer specifically developed to detect brain neurofibrillary tau pathology, has the potential to facilitate accurate diagnosis of Alzheimer's disease (AD), staging of brain tau burden and monitoring disease progression. Recent PET studies show that patients with mild cognitive impairment and AD dementia exhibit significantly higher in vivo [F-18]-AV-1451 retention than cognitively normal controls. Importantly, PET patterns of [F-18]-AV-1451 correlate well with disease severity and seem to match the predicted topographic Braak staging of neurofibrillary tangles (NFTs) in AD, although this awaits confirmation. We studied the correlation of autoradiographic binding patterns of [F-18]-AV-1451 and the stereotypical spatiotemporal pattern of progression of NFTs using legacy postmortem brain samples representing different Braak NFT stages (I-VI). We performed [F-18]-AV-1451 phosphor-screen autoradiography and quantitative tau measurements (stereologically based NFT counts and biochemical analysis of tau pathology) in three brain regions (entorhinal cortex, superior temporal sulcus and visual cortex) in a total of 22 cases: low Braak (I-II, n = 6), intermediate Braak (III-IV, n = 7) and high Braak (V-VI, n = 9). Strong and selective [F-18]-AV-1451 binding was detected in all tangle-containing regions matching precisely the observed pattern of PHF-tau immunostaining across the different Braak stages. As expected, no signal was detected in the white matter or other non-tangle containing regions. Quantification of [F-18]-AV-1451 binding was very significantly correlated with the number of NFTs present in each brain region and with the total tau and phospho-tau content as reported by Western blot and ELISA. [F-18]-AV-1451 is a promising biomarker for in vivo quantification of brain tau burden in AD. Neuroimaging-pathologic studies conducted on postmortem material from individuals imaged while alive are now needed to confirm these observations.