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

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Carlos A Ribeiro (Author) Other; Sandra Marisa Oliveira (Author) Other; Luis F Guido (Author) FCUP; Ana Magalhaes (Author) Other; Gregorio Valencia (Author) Other; Gemma Arsequell (Author) Other; Maria Joao Saraiva (Author) Other; Isabel Cardoso (Author) Other

Journal

Title: Journal of Alzheimer's Disease

Vol. 39

ISSN: 1387-2877

Publisher: IOS PRESS

Indexing

ISI Web of Knowledge - 42 Citations

Scopus - 42 Citations

Scientific classification

FOS: Medical and Health sciences > Health sciences

Other information

Authenticus ID: P-009-5CB

Abstract (EN): 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-beta (A beta) interaction. Small compounds, TTR stabilizers (usually non-steroid anti-inflammatory drugs), bind to the thyroxine (T-4) central binding channel, increasing TTR tetrameric stability and TTR/A beta interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/A beta interaction, iododiflunisal (IDIF), in A beta deposition and other AD features, using A beta PPswe/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 A beta 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, A beta levels were reduced in plasma suggesting TTR promoted A beta 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.

Language: English

Type (Professor's evaluation): Scientific