Cortical laminar tau deposits and activated astrocytes in Alzheimer’s disease visualised by 3H-THK5117 and 3H-deprenyl autoradiography

Abstract

Hyperphosphorylated tau protein deposits and, inflammatory processes are characteristic components of Alzheimer disease (AD) pathology. We here aimed to visualize in vitro the distribution of tau deposits and activated astrocytes across the cortical layers in autopsy AD brain tissue using the radiotracers 3H-THK5117 and 3H-deprenyl. 3H-THK5117 and 3H-deprenyl autoradiographies were carried out on frozen brain sections from three AD patients and one healthy control. 3H-THK5117 showed a distinct laminar cortical binding similar to 3H-deprenyl autoradiography, with an extensive binding in the superficial and deep layers of the temporal neocortices, whereas the middle frontal gyrus showed an even binding throughout the layers. Globally, eventhough some differences could be observed, AT8 (tau) and GFAP (astrocyte) immunostaining showed a laminar pattern comparable to their corresponding radiotracers within each AD case. Some variability was observed between the AD cases reflecting differences in disease phenotype. The similar laminar cortical brain distribution of tau deposits and activated astrocytes supports the hypothesis of a close pathological interconnection. The difference in regional binding patterns of 3H-THK5117 and AT8 antibody staining suggest additional tau binding sites detectable by 3H-THK5117.

Involvement of Astrocytes in Alzheimer’s Disease from a Neuroinflammatory and Oxidative Stress Perspective

“…Similar results have been obtained in other studies using (11)C-deuterium- L -deprenyl, where astrocytosis is prominent at the initial phases, even at preclinical stages, and then declines as the disease progresses ( Carter et al, 2012 ; Schöll et al, 2015 ; Rodriguez-Vieitez et al, 2016b ). In addition, a similar laminar binding pattern for tau and [3H] L -deprenyl at the temporal lobe was recently demonstrated, suggesting tau deposits and astrocytic inflammatory processes are closely related in AD ( Lemoine et al, 2017 ). All these results point to an early contribution of astrocytes in AD pathology.…”

Tau positron emission tomography imaging in tauopathies: The added hurdle of off‐target binding

“…We can cite, for example, [ 3 H]deprenyl specifically targeting the MAO-B enzyme, for which autoradiography on paraffin sections cannot be performed, most probably due to damage to the enzyme during the paraffin embedding process. In our in vitro studies, we demonstrated that while [ 3 H]deprenyl and [ 3 H]THK5117 showed a similar cortical laminar distribution, they were not competing at the concentration range used in PET studies (4 nM), indicating that they do not bind to the same site, or at least not with the same affinity [25] . Moreover, while the highest MAO-B inhibition of [ 18 F]THK5351 binding reported by Ng et al.…”

MAO-B Inhibitors Do Not Block In Vivo Flortaucipir([18F]-AV-1451) Binding

“…Finally, as none of our Parkinson's disease patients appeared to be tau-positive, we were unable to investigate if the specific binding from areas with neurofibrillary tangles was blockable with MAO-B inhibitors [9,35].…”