title: Transthyretin and the brain re-visited: is neuronal synthesis of transthyretin protective in Alzheimer's disease?
abstract: Since the mid-1990's a trickle of publications from scattered independent laboratories have presented data suggesting that the systemic amyloid precursor transthyretin (TTR) could interact with the amyloidogenic β-amyloid (Aβ) peptide of Alzheimer's disease (AD). The notion that one amyloid precursor could actually inhibit amyloid fibril formation by another seemed quite far-fetched. Further it seemed clear that within the CNS, TTR was only produced in choroid plexus epithelial cells, not in neurons. The most enthusiastic of the authors proclaimed that TTR sequestered Aβ in vivo resulting in a lowered TTR level in the cerebrospinal fluid (CSF) of AD patients and that the relationship was salutary. More circumspect investigators merely showed in vitro interaction between the two molecules. A single in vivo study in Caenorhabditis elegans suggested that wild type human TTR could suppress the abnormalities seen when Aβ was expressed in the muscle cells of the worm. Subsequent studies in human Aβ transgenic mice, including those from our laboratory, also suggested that the interaction reduced the Aβ deposition phenotype. We have reviewed the literature analyzing the relationship including recent data examining potential mechanisms that could explain the effect. We have proposed a model which is consistent with most of the published data and current notions of AD pathogenesis and can serve as a hypothesis which can be tested.
authors: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Rd,, MEM-230, La Jolla, CA 92037, USA.
authors: Xinyi
authors: X
authors: Li
authors: Joel N
authors: JN
authors: Buxbaum
mesh_terms: D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D011228:Prealbumin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D011228:Prealbumin