Transthyretin is one of a handful of proteins that, like amyloid-β, can adopt a β-sheet conformation and aggregate as amyloid. So it may seem counterintuitive that transthyretin could be used to prevent Aβ toxicity, yet that is exactly the proposition of a paper in this week’s PNAS online. Researchers led by Joel Buxbaum at The Scripps Research Institute, La Jolla, California, report that transthyretin (TTR) protects against Aβ pathology in mice. They suggest that TTR works like a chaperone and hint that this activity might lead to new therapeutic approaches to treating Alzheimer disease.
Transthyretin is a serum and cerebrospinal fluid (CSF) carrier that binds thyroid hormones and other small molecules. It also binds to Aβ in the CSF (see Schwarzman et al., 1994), is found adjacent to Aβ plaques in transgenic mice, and prevents Aβ aggregation in C. elegans (see Link, 1995). In addition, Aβ deposition speeds up when one copy of TTR is deleted in APP/presenilin double transgenic (APPSwe/PS1δE9) mice (see Choi et al., 2007), so the idea that transthyretin may be protective in AD is not new. Now, Buxbaum and colleagues show that overexpressing TTR is also protective in mice and that TTR physically binds to Aβ, which supports the notion that “increasing cerebral TTR synthesis is a potential therapeutic/prophylactic approach to human AD,” as the authors suggest.
Buxbaum and colleagues evaluated the offspring of APP23 transgenic mice (expressing human APP carrying the Swedish mutation) crossed with animals overexpressing human TTR. They also evaluated what happens when TTR is missing by testing APP23 mice generated in a mouse TTR-negative background. The investigators found that overexpressing human TTR protects mice against cognitive and spatial deficits. In the Barnes maze test, 15-month-old APP23 animals had more errors and fared more poorly in finding the escape hole than did wild-type animals. APP23 mice overexpressing human TTR performed about as well as wild-type controls, indicating a protective effect of transthyretin. Lack of endogenous mouse TTR had the opposite effect. Younger (5.5 months old) APP23 mice performed about as well as controls, but in the absence of mouse TTR the animals made significant errors.
Immunohistochemical analysis indicates that these behavioral changes are related to Aβ pathology. While APP23 animals normally have Aβ deposits by 16 months, three out of 24 APP23/hTTR animals had no detectable deposits by that age, and in those that had detectable deposits, they were significantly fewer (around half), and soluble Aβ levels were also about half compared to control APP23 animals. In contrast, the researchers found detectable Aβ deposits in seven of 11 5.5-month-old APP23 mice lacking endogenous TTR—Aβ deposits are normally very rare in mice at that age. The amount of formic acid-soluble Aβ was nearly doubled in the mTTR-negative mice as well.
Correlating Aβ levels and deposits with TTR does mean the two proteins react physically, but the researchers showed, using surface plasmon resonance, that TTR interacts with Aβ monomers (both Aβ40 and Aβ42) and fibrils. Interestingly, mouse TTR had much higher affinity for any Aβ form than did human TTR.
All told, the findings indicate that TTR can ameliorate the pathology and behavioral symptoms associated with Aβ overproduction in a mammalian model. “It appears that the interaction is physical and that TTR may behave in a chaperone-like manner for molecular species of Aβ larger than monomers. The observations support the novel notion that increasing cerebral TTR synthesis is a potential therapeutic/prophylactic approach to human AD,” write the authors.—Tom Fagan