Abstract
BackgroundWhile still controversial, it has been demonstrated that vascular defects can precede the onset of other AD hallmarks features, making it an important therapeutic target. Given that the protein transthyretin (TTR) has been established as neuroprotective in AD, here we investigated the influence of TTR in the vasculature.MethodsWe evaluated the thickness of the basement membrane and the length of brain microvessels, by immunohistochemistry, in AβPPswe/PS1A246E (AD) transgenic mice and non-transgenic mice (NT) bearing one (TTR+/−) or two (TTR+/+) copies of the TTR gene. The angiogenic potential of TTR was evaluated in vitro using the tube formation assay, and in vivo using the chick chorioallantoic membrane (CAM) assay.ResultsAD transgenic mice with TTR genetic reduction, AD/TTR+/−, exhibited a thicker BM in brain microvessels and decreased vessel length than animals with normal TTR levels, AD/TTR+/+. Further in vivo investigation, using the CAM assay, revealed that TTR is a pro-angiogenic molecule, and the neovessels formed are functional. Also, TTR increased the expression of key angiogenic molecules such as proteins interleukins 6 and 8, angiopoietin 2, and vascular endothelial growth factor, by endothelial cells, in vitro, under tube formation conditions. We showed that while TTR reduction also leads to a thicker BM in NT mice, this effect is more pronounced in AD mice than in NT animals, strengthening the idea that TTR is a neuroprotective protein. We also studied the effect of TTR tetrameric stabilization on BM thickness, showing that AD mice treated with the TTR tetrameric stabilizer iododiflunisal (IDIF) displayed a significant reduction of BM thickness and increased vessel length, when compared to non-treated littermates.ConclusionOur in vivo results demonstrate the involvement of TTR in angiogenesis, particularly as a modulator of vascular alterations occurring in AD. Since TTR is decreased early in AD, its tetrameric stabilization can represent a therapeutic avenue for the early treatment of AD through the maintenance of the vascular structure.
Highlights
Alzheimer’s disease (AD) patients undergo several neurovascular changes at different levels
The TTR+/− animals, in particular, the AD/TTR+/−, are a better representation of the behavior of TTR in AD, since TTR is decreased in this pathology but not absent
Our results revealed a significantly thicker collagen IV layer in 7-months old AD/TTR+/− as compared to AD/TTR+/+ animals, both in cortex and in hippocampus microvessels (Fig. 1 A1)
Summary
Alzheimer’s disease (AD) patients undergo several neurovascular changes at different levels. The reduction of the capillary density is characteristic of the AD brains [5] This is due to an aberrant angiogenesis with premature pruning of capillary networks. Other authors describe increased vascular density in AD [7], the underlying angiogenic process has pathological characteristics. Other authors argue that the accumulation of Aβ in the walls of the capillaries can contribute to the reduced brain capillary density in AD via anti-angiogenic activity [9, 10]. Another observed alteration in AD is the increased thickness of the vascular BM in AD [11]. Given that the protein transthyretin (TTR) has been established as neuroprotective in AD, here we investigated the influence of TTR in the vasculature
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