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Transthyretin and the Brain Re-Visited: Is Neuronal Synthesis of Transthyretin Protective in Alzheimer’S Disease? Xinyi Li and Joel N Buxbaum*

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Transthyretin and the Brain Re-Visited: Is Neuronal Synthesis of Transthyretin Protective in Alzheimer’S Disease? Xinyi Li and Joel N Buxbaum* Li and Buxbaum Molecular Neurodegeneration 2011, 6:79 http://www.molecularneurodegeneration.com/content/6/1/79 REVIEW Open Access Transthyretin and the brain re-visited: Is neuronal synthesis of transthyretin protective in Alzheimer’s disease? Xinyi Li and Joel N Buxbaum* 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 b- amyloid (Ab) 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 Ab 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 Ab was expressed in the muscle cells of the worm. Subsequent studies in human Ab transgenic mice, including those from our laboratory, also suggested that the interaction reduced the Ab 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. Keywords: Beta-amyloid precursor protein (AβPP, APP), Beta-amyloid (Aβ), Alzheimer’s disease (AD), Transthyretin (TTR), Amyloidosis, Protein homeostasis, Aggregation Introduction influence whether a protein will aggregate in vivo [3,4]. All amyloid fibrils are similar in appearance, displaying The frequency of many of the amyloidoses increases Congophilic, non-branching fibrils 7.5-10 nm in dia- with aging but their deposition appears to be indepen- meter. The twenty nine (thus far) identified human dent, i.e. each has its own anatomically predisposed site amyloid precursors [1] share no primary sequence and and pattern [5]. Thus, while there are reported instances no common conformation although recent biophysical of mixed precursor deposition, they are relatively studies suggest the presence of conformationally/energe- uncommon, e.g. [6-9]. Nonetheless the commonality of tically similar repeat subunits which determine whether structure that leads precursor proteins to form fibrils a given protein belongs to the “amylome” [2]. Further it suggests that interaction could occur, perhaps accelerat- has been suggested that while the precursors represent a ing fibril formation. The example of transthyretin (TTR) variety of folded and unfolded native structures, a com- and b-amyloid (Ab) raises the question as to whether bination of primary structural features and level of the effect may be, in truth, to reduce fibrillogenesis. expression determines the ordering of proteins along a Wild type and mutant forms of TTR are the precur- proposed “edge of stability” under in vivo conditions, i.e. sors in the systemic human diseases, Familial Amyloido- there are both qualitative and quantitative factors that tic Polyneuropathy (FAP), Familial Amyloidotic Cardiomyopathy (FAC) and Senile Systemic Amyloidosis ’ * Correspondence: [email protected] (SSA) [10]. In contrast, Alzheimer s disease (AD) is a Department of Molecular and Experimental Medicine, The Scripps Research localized amyloid disease of the brain. AD and the TTR Institute, 10550 North Torrey Pines Rd., MEM-230, La Jolla, CA 92037, USA © 2011 Li and Buxbaum; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Li and Buxbaum Molecular Neurodegeneration 2011, 6:79 Page 2 of 17 http://www.molecularneurodegeneration.com/content/6/1/79 amyloidoses share age dependence and are manifested cortex, the regions associated with cognition and mem- as both autosomal dominant, mutation-related and ory (reviewed in [20]). In addition inflammation sporadic (wild type protein associated) diseases. In the (reviewed in [21,22]), oxidative damage (reviewed in TTR amyloidoses the precursor is synthesized primarily [23-25]) and reactive gliosis [26] are evident in AD by hepatocytes distant from the main sites of deposition brains. in peripheral nerve and heart. However local synthesis The precise molecular mechanisms responsible for the and deposition can be seen in the eye, gut, kidney and pathology of AD are still unclear although there is no choroid plexus. In AD the b-amyloid precursor protein lack of reasonable models. Since the original isolation (AbPP) is synthesized ubiquitously but deposition and and identification of Ab and AbPP, the weight of clinical tissue compromise are restricted to the brain and even and experimental evidence supports a major, if not pri- more so to specific brain regions. mary role for Ab in the development of AD (reviewed The first association of TTR with AD was the observa- in [27-29]). Whether it is the ultimate source of the tion that cerebrospinal fluid (CSF) could inhibit Ab fibril pathology is uncertain but the evidence for involvement formation in vitro [11]. TTR [12] was the third CSF pro- of AbPP in AD pathogenesis is convincing. tein found to interact with Ab after apolipoprotein E (ApoE) [13] and ApoJ (or clusterin) [14]. It was AbPP processing pathways hypothesized at that time that these three extracellular AbPP is a 695-770 amino acid glycosylated membrane proteins could “sequester” Ab, thereby preventing neu- protein with a single hydrophobic transmembrane ronal damage, although there was little evidence pre- domain of 23 residues [30]. A large hydrophilic amino- sented as to how or where such sequestration could ectodomain of AbPP is cleaved by a-orb-secretase to take place. Perhaps “chaperone” in the sense of “protec- produce secreted AbPP fragments, sAPPa or sAPPb, tor” might have been a better term than “sequester”, but respectively [31] (see Figure 1). Alpha-secretase is a the oxymoronic phrase “pathologic chaperone” had member of the ADAM (a disintegrin and metallopro- already been utilized to describe the co-deposition of tease) family of proteases anchored in the cell mem- ApoE in AD plaques [15]. brane [32-36], which includes ADAM9 [33], ADAM10 Results of the early experiments supporting the asso- [35], ADAM17 (also known as tumour necrosis factor-a ciation and suggesting that the interaction could be ben- convertase, TACE) [37] and ADAM19 [36]. The sAPPa eficial were suspect because of reservations concerning fragment appears to be involved in the development of methodology. Further, the notion that an in vivo sys- the nervous system, promoting neurite outgrowth temic amyloid precursor could have a salutary effect on [38,39], synaptogenesis [40,41], enhancing memory for- the course of another, albeit local, form of amyloidosis, mation [42], and providing neuro-protection against derived from a different precursor, taking place in a dif- excitotoxic stimuli [43] and metabolic and oxidative ferent, relatively closed anatomic compartment seemed insults [44] (For review see [45]). counterintuitive. Lastly the published evidence that TTR Beta-secretase (BACE-1) is a predominantly b-site was not a neuronal protein, but synthesized in choroid amyloid precursor protein-cleaving aspartyl-protease plexus epithelium made it seem unlikely that it could [46,47]. However the earlier notion that BACE-1 is the have much to do with the primarily neuronal degenera- only b-secretase activity protease in vivo [48,49] has tive process produced by aggregation of a protein pro- been challenged [50-52]. The BACE-1 cleavage product, duced in/by neurons [16]. sAPPb, does not have the same neuroprotective proper- We will review the relevant published papers that have ties as sAPPa. It has been recently shown that upon contributed to our current knowledge regarding the further cleavage, sAPPb releases a 35 kDa amino term- relationship between TTR and AD. We will try to point inal fragment (N-APP), representing amino acids 1-286 out the inconsistencies that have cast doubt on the of AbPP, that behaves as a ligand for neuronal death pathogenetic importance of the connections and we will receptor 6 (DR6) [53]. That molecule has been hypothe- present hypotheses that have been proposed to account sized to be involved in pruning of synapses during for the interaction. development of both central and peripheral neurons [53]. The investigators suggested that aberrant activation Alzheimer’s Disease of the “death signal” could play a role in AD pathogen- The neuropathologic hallmarks of human AD include esis but there is no published direct evidence for such extracellular senile plaques consisting primarily of fibrils an effect in AD (Figure 1). representing aggregated Ab peptides, intracellular neu- Alpha and b cleavages also yield small cytoplasmic rofibrillary tangles composed of hyperphosphorylated carboxy-terminal fragments (CTF’s), CTF83 and CTF99, microtubule-binding tau protein [17-19], and synaptic respectively. In the so-called
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