Oral treatment with iododiflunisal delays beta amyloid plaque formation in a transgenic mouse model of Alzheimer Disease: a Longitudinal in vivo molecular imaging study

Abstract

Background: Transthyretin (TTR) is a tetrameric, Amyloid-beta (Aβ)-binding protein, which has been shown to reduce Aβ toxicity both in vitro and in vivo. The ability of TTR to interact with Aβ can be enhanced by a series of small molecules that stabilize its tetrameric form. Because of this, TTR stabilizers might act as disease modifying drugs in Alzheimer Disease (AD). In this work, we monitored the therapeutic efficacy of two TTR stabilizers, iododiflunisal (IDIF) and the repurposed drug tolcapone, by longitudinal assessment of Aβ deposition in an animal model of AD using positron emission tomography (PET) with [ 18 F]florbetaben.Methods: Mice (AβPPswe/PS1A246E/TTR+/-; n=21) were divided into 3 groups (n=7 per group): iododiflunisal (IDIF)-treated, tolcapone-treated and non-treated. The treatment, administered in the drinking water at a dose of 100 mg/Kg/day, was started at 5 months of age. The level of Aβ deposition was assessed at ages=5, 9, 11, and 14 months by PET imaging using [ 18 F]florbetaben. Treatment efficacy was determined based on radiotracer uptake in the hippocampus (HIP) and the cortex (CTX) with respect to the cerebellum (CB) and presented as standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analysis was performed at 14 months of age to further support in vivo results. Results: SUVr of [ 18 F]florbetaben in CTX and HIP of non-treated animals progressivelyincreased from age=5 to 11 months and stabilized afterwards. In contrast, [ 18 F]florbetaben uptake in HIP of IDIF-treated animals remained constant between ages=5 and 11 months and significantly increased at 14 months. At age=11 months, IDIF-treated group showed significantly lower SUVr values than those obtained for nontreated animals. In tolcapone-treated group, SUVr progressively increased with time, but at lower rate than in non-treated group. Moderate treatment effect of tolcapone suggests different mechanism of action than IDIF. No significant treatment effect was observed in CTX of IDIF-or tolcapone-treated animals. Results from IHC matched the in vivo data at age=14 months. Conclusions:The TTR stabilizer IDIF shows good Aβ-protective effect. Nevertheless, Aβ levels in treated and control animals reached similar values at the end of the study. Furthermore, differences in efficacy between IDIF and tolcapone, suggest different mechanisms of action.

An Assay for Screening Potential Drug Candidates for Alzheimer's Disease That Act as Chaperones of the Transthyretin and Amyloid‐β Peptides Interaction

“…The amyloid peptide sequences Ab (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) and Ab (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) were purchased from Bachem AG (Switzerland) as trifluoroacetate salts (ref.…”

“…By recent radiochemical studies, we have proven that preformed TTR‐IDIF labeled complexes better penetrate the blood brain barrier (BBB) than free TTR and IDIF [10] . By longitudinal in vivo molecular imaging study we have shown that oral treatment with IDIF in a transgenic mouse model of AD delays hippocampal amyloid beta formation [11] …”

“…[10] By longitudinal in vivo molecular imaging study we have shown that oral treatment with IDIF in at ransgenic mouse model of AD delays hippocampal amyloid beta formation. [11] To elucidatea tt he molecular level the mechanismsi nvolved in these TTR/Ab/IDIF interactions by biophysical methods we have used saturation-transfer difference nuclear magnetic resonance (STD-NMR) techniques that have allowed us to identify the 17-mer peptide sequence Ab(12-28)a st he main structural recognition motif. [12] Interestingly,t his short Ab amyloid peptide (VHHQKLVFFAEDVGSNK) has been extensively studied and is reportedt oe xhibit essentially identical neurotoxic behavior and fibril formation features as the Ab(1-42)a nd (1-40) peptides and thus has been used as as hort model of the full Ab peptides (Supporting information).…”

Targeting transthyretin in Alzheimer's disease: Drug discovery of small-molecule chaperones as disease-modifying drug candidates for Alzheimer's disease

“…44 We have demonstrated by early in vitro studies that TTR and Aβ bind together and that this interaction can be enhanced by a small set of TTR tetramer-stabilizing compounds, 45 one of them iododiflunisal (IDIF), a iodinated analog of the NSAID diflunisal (DIF) (Figure 1). [46][47][48] More importantly, in vivo administration of IDIF to a mouse model of AD, resulted in decreased brain Aβ levels and deposition, 49,50 and improving the cognitive functions that are impaired in this AD-like neuropathology. 49 Drug repurposing of already known drugs for new indications is a drug discovery approach increasingly being used to search for new therapies for diseases with unmet clinical needs.…”