Journal
SCIENTIFIC REPORTS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-019-50071-w
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Funding
- Fundacio Marato de TV3 [20140330-31-32-33-34]
- MINECO (Spain) [CTQ201787637-R]
- Foundation for Science and Technology (FCT, Portugal)
- European Social Fund (ESF) through the Human Potential Operational Programme (HPOP), type 4.2 -Promotion of Scientific Employment
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It is well settled that the amyloidogenic properties of the plasma protein transporter transthyretin (TTR) can be modulated by compounds that stabilize its native tetrameric conformation. TTR is also present in cerebrospinal fluid where it can bind to A beta-peptides and prevent A beta aggregation. We have previously shown that treatment of Alzheimer's Disease (AD) model mice with iododiflunisal (IDIF), a TTR tetramer stabilizing compound, prevents AD pathologies. This evidence positioned IDIF as a new lead drug for AD. In dissecting the mechanism of action of IDIF, we disclose here different labeling strategies for the preparation of I-131-labeled IDIF and I-131- and I-124-labeled TTR, which have been further used for the preparation of IDIF-TTR complexes labeled either on the compound or the protein. The biodistribution of all labeled species after intravenous administration has been investigated in mice using ex vivo and in vivo techniques. Our results confirm the capacity of TTR to cross the blood brain barrier (BBB) and suggest that the formation of TTR-IDIF complexes enhances BBB permeability of both IDIF and TTR. The increased TTR and IDIF brain concentrations may result in higher A beta-peptide sequestration capacity with the subsequent inhibition of AD symptoms as we have previously observed in mice.
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