The choroid plexus (CP), located in each of the four ventricles of the brain, is formed by a monolayer of epithelial cells that surrounds a highly vascularized connective tissue with permeable capillaries. These cells are joined by tight junctions forming the blood–cerebrospinal fluid barrier (BCSFB), which strictly regulates the exchange of substances between the blood and cerebrospinal fluid (CSF). The primary purpose of the CP is to secrete CSF, but it also plays a role in the immune surveillance of the central nervous system (CNS) and in the removal of neurotoxic compounds from the CSF. According to recent findings, the CP is also involved in the modulation of the circadian cycle and neurogenesis. In diseases such as Alzheimer’s disease (AD), the function of the CP is impaired, resulting in an altered secretory, barrier, transport, and immune function. This review describes the current state of knowledge concerning the roles of the CP and BCSFB in the pathophysiology of AD and summarizes recently proposed therapies that aim to restore CP and BCSFB functions.

Background: While 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.Methods: We 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.Results: AD 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.Conclusion: Our 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.

Transthyretin (TTR) is a plasma protein known as a transporter of thyroxine and retinol but also can inhibit the formation of amyloid β-peptide (Aβ) fibrils and catalyze the proteolysis of apolipoprotein A-I and Aβ. Here, recombinant TTR is shown to have proteolytic activity against specific conformations of α-synuclein (aSyn), a protein that accumulates in intraneuronal inclusions characteristic of Parkinson’s disease (PD). Our discovery stemmed from the observation of a marked decrease in aSyn aggregation in the presence of submicromolar concentrations of TTR. Using integrated biophysical techniques, including advanced microscopy and mass spectrometry, we found that aSyn aggregation is prevented due to the proteolytic cleavage of free aSyn by TTR, in a reaction that is slower for S-glutathionylated TTR and faster for TTR preparations containing vestigial amounts of ∼70 kDa TTR oligomers (oTTR). Interestingly, this proteolysis-trigger effect is not unique to oTTR since it can also be induced by Teflon and glass surfaces independently of which TTR preparation is tested. Our results indicate that a change in aSyn conformation must precede the proteolysis step. The proteolysis of misfolded aSyn emerges as a possible TTR function with implications for the understanding of different neurodegenerative disorders.

Background In the last few decades, Transthyretin (TTR) has gained attention due to its implication in brain functions and neurodegenerative conditions, such as Alzheimer’s Disease (AD) by modulating amyloid-beta (Aβ) pathology. This study aims to assess TTR levels and tetrameric instability in both plasma and cerebrospinal fluid (CSF) across the clinical continuum of AD, and to establish associations between TTR and key AD biomarkers, to enhance our understanding of the role of TTR in AD pathogenesis. Methods We conducted an evaluation of TTR levels and tetrameric instability in plasma and CSF in mild cognitive impairment (MCI-AD, n=29) and Dementia-AD (n=37) patients and examined the association with clinical, biochemical and genetic data. Results Key findings revealed a substantial decrease in plasma TTR levels in the Dementia-AD patients compared to the MCI-AD group, with a pronounced gender-specific effect identified in women, while no differences were detected in the CSF. The search for associations identified several correlations amongst MCI-AD patients where CSF TTR levels inversely correlated with markers of amyloid pathology and neurodegeneration such as Aβ40 (r=-0.43, p < 0.02), p-Tau181 (r=-0.54, p < 0.03), t-Tau (r=-0.57, p< 0.001) and NfL (r=-0.49, p<0.006). CSF TTR instability also correlated negatively with CSF Aβ42 (r=-0.6, p<0.001) and Aβ42/Aβ40 ratio (r=-0.58, p<0.001), indicating an association with increased amyloid burden. In the Dementia-AD group, plasma TTR levels correlated negatively with GFAP (r=-0.4, p<0.014), reflecting potential links with neuroinflammation. Additionally, plasma TTR instability correlated with CSF TTR instability (r=0.42, p < 0.009) and tau pathology markers (p-Tau181 (r=0.38, p < 0.02) and t-Tau (r=0.42, p<0.09)). Given the strong association between CSF TTR instability and Aβ42, we investigated the effect of the peptide on TTR tetrameric instability and showed a clear increase in TTR instability in samples incubated with Aβ42 for 24 hours (p<0.05). Conclusions This study emphasizes several associations between TTR and other key indicators of AD and suggests TTR is associated with Aβ clearance, neurodegeneration, and neuroinflammation across different stages of the disease. We propose Aβ42 and its increase in the brain as a factor destabilizing the TTR tetrameric fold, resulting in TTR impaired function.

While still controversial, it has been demonstrated that vascular defects can precede the onset of the 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. AD 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 chick chorioallantoic membrane (CAM) assay, revealed that TTR is a pro-angiogenic molecule. Also, TTR increased the expression of key angiogenic molecules, by endothelial cells under tube formation conditions. We showed that TTR reduction leads to a thicker BM 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 iododiflunisal (IDIF) displayed a significant reduction of BM thickness and increased vessel length when compared to non-treated littermates. Our in vivo results show 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.