Transthyretin Stabilization by Iododiflunisal Promotes Amyloid-β Peptide Clearance, Decreases its Deposition, and Ameliorates Cognitive Deficits in an Alzheimer's Disease Mouse Model

Article type: Research Article

Authors: Ribeiro, Carlos A.^{a; b} | Oliveira, Sandra Marisa^a | Guido, Luis F.^c | Magalhães, Ana^a | Valencia, Gregorio^d | Arsequell, Gemma^d | Saraiva, Maria João^{a; b} | Cardoso, Isabel^{a; *}

Affiliations: [a] Molecular Neurobiology, IBMC- Instituto de Biologia Molecular e Celular, Porto, Portugal | [b] ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal | [c] REQUIMTE – Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal | [d] Institut de Química Avançada de Catalunya (IQAC-CSIC), Barcelona, Spain

Correspondence: [*] Correspondence to: Isabel dos Santos Cardoso, Molecular Neurobiology, IBMC, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal. Tel.: +351 22 6074900; Fax: +351 22 6099157; E-mail: [email protected].

Abstract: Alzheimer's disease (AD) is the most common form of dementia and now represents 50–70% of total dementia cases. Over the last two decades, transthyretin (TTR) has been associated with AD and, very recently, a novel concept of TTR stability has been established in vitro as a key factor in TTR/amyloid-β (Aβ) interaction. Small compounds, TTR stabilizers (usually non-steroid anti-inflammatory drugs), bind to the thyroxine (T4) central binding channel, increasing TTR tetrameric stability and TTR/Aβ interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/Aβ interaction, iododiflunisal (IDIF), in Aβ deposition and other AD features, using AβPPswe/PS1A246E transgenic mice, either carrying two or just one copy of the TTR gene (AD/TTR+/+ or AD/TTR+/−, respectively), available and characterized in our laboratory. The results showed that IDIF administered orally bound TTR in plasma and stabilized the protein, as assessed by T4 displacement assays, and was able to enter the brain as revealed by mass spectrometry analysis of cerebrospinal fluid. TTR levels, both in plasma and cerebrospinal fluid, were not altered. In AD/TTR+/− mice, IDIF administration resulted not only in decreased brain Aβ levels and deposition but also in improved cognitive function associated with the AD-like neuropathology in this mouse model, although no improvements were detectable in the AD/TTR+/+ animals. Further, in AD/TTR+/− mice, Aβ levels were reduced in plasma suggesting TTR promoted Aβ clearance from the brain and from the periphery. Taken together, these results strengthen the importance of TTR stability in the design of therapeutic drugs, highlighting the capacity of IDIF to be used in AD treatment to prevent and to slow the progression of the disease.

Keywords: Alzheimer's disease, amyloid-β peptide, behavior, cerebrospinal fluid, iododiflunisal, plasma, transgenic mouse, transthyretin

DOI: 10.3233/JAD-131355

Journal: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 357-370, 2014