|Title||Transferrin Receptor-Mediated Uptake at the Blood-Brain Barrier Is Not Impaired by Alzheimer's Disease Neuropathology.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Auteurs||Bourassa, P, Alata, W, Tremblay, C, Paris-Robidas, S, Calon, F|
|Date Published||2019 Feb 04|
The transferrin receptor (TfR) is highly expressed by brain capillary endothelial cells (BCECs) forming the blood-brain barrier (BBB) and is therefore considered as a potential target for brain drug delivery. Monoclonal antibodies binding to the TfR, such as clone Ri7, have been shown to internalize into BCECs in vivo. However, since Alzheimer's disease (AD) is accompanied by a BBB dysfunction, it raises concerns about whether TfR-mediated transport becomes inefficient during the progression of the disease. Measurements of TfR levels using Western blot analysis in whole homogenates from human post-mortem parietal cortex and hippocampus did not reveal any significant difference between individuals with or without a neuropathological diagnosis of AD (respectively, n = 19 and 22 for the parietal cortex and n = 12 and 14 for hippocampus). Similarly, TfR concentrations in isolated human brain microvessels from parietal cortex were similar between controls and AD cases. TfR levels in isolated murine brain microvessels were not significantly different between groups of 12- and 18-month-old NonTg and 3xTg-AD mice, the latter modeling Aβ and τ neuropathologies. In situ brain perfusion assays were then conducted to measure the brain uptake and internalization of fluorolabeled Ri7 in BCECs upon binding. Consistently, TfR-mediated uptake in BCECs was similar between 3xTg-AD mice and nontransgenic controls (∼0.3 μL·g·s) at 12, 18, and 22 months of age. Fluorescence microscopy analysis following intravenous administration of fluorolabeled Ri7 highlighted that the signal from the antibody was widely distributed throughout the cerebral vasculature but not in neurons or astrocytes. Overall, our data suggest that both TfR protein levels and TfR-dependent internalization mechanisms are preserved in the presence of Aβ and τ neuropathologies, supporting the potential of TfR as a vector target for drug delivery into BCECs in AD.
|Alternate Journal||Mol. Pharm.|