Modulating Role of TTR in Aβ Toxicity, from Health to Disease

Amyloidosis is a generic term that refers to a wide spectrum of diseases that are characterized by the deposition of proteins in different organs, forming insoluble aggregates. Examples include islet amyloid polypeptide (IAPP) associated with diabetes type 2, prion protein (PrP) related with spongiform encephalopathies, (TTR) associated with familial amyloidotic polyneuropathy (FAP), and amyloid-beta (Aβ) peptide linked to Alzheimer’s disease (AD), the most common form of dementia. Aβ peptide, thought to be the causative agent in AD, is generated upon sequential cleavage of the amyloid precursor protein (APP), by beta- and gamma-secretases, and it is believed that an imbalance between Aβ production and clearance results in its accumulation in the brain. TTR is a 55 kDa homotetrameric protein synthesized by the liver and choroid plexus of the brain and is involved in the transport of thyroid hormones and retinol. TTR protects against Aβ toxicity by binding the peptide, thus inhibiting its aggregation. Also, increased Aβ levels are found in both brain and plasma of AD mice with only one copy of the TTR gene, when compared to animals with two copies of the gene, suggesting a role for TTR in Aβ clearance. Growing evidence also suggests a wider role for TTR in central nervous system neuroprotection, including in the cases of ischemia, regeneration, and memory

Radiochemical examination of transthyretin (TTR) brain penetration assisted by iododiflunisal, a TTR tetramer stabilizer and a new candidate drug for AD

It is well settled that the amyloidogenic properties of the plasma protein transporter transthyretin (TTR) can be modulated by compounds that stabilize its native tetrameric conformation. TTR is also present in cerebrospinal fluid where it can bind to Aβ-peptides and prevent Aβ aggregation. We have previously shown that treatment of Alzheimer’s Disease (AD) model mice with iododiflunisal (IDIF), a TTR tetramer stabilizing compound, prevents AD pathologies. This evidence positioned IDIF as a new lead drug for AD. In dissecting the mechanism of action of IDIF, we disclose here different labeling strategies for the preparation of 131I-labeled IDIF and 131I- and 124I-labeled TTR, which have been further used for the preparation of IDIF-TTR complexes labeled either on the compound or the protein. The biodistribution of all labeled species after intravenous administration has been investigated in mice using ex vivo and in vivo techniques. Our results confirm the capacity of TTR to cross the blood brain barrier (BBB) and suggest that the formation of TTR-IDIF complexes enhances BBB permeability of both IDIF and TTR. The increased TTR and IDIF brain concentrations may result in higher Aβ-peptide sequestration capacity with the subsequent inhibition of AD symptoms as we have previously observed in mice. © 2019, The Author(s).The work was supported by a grant from the Fundació Marató de TV3 (Neurodegenerative Diseases Call, Project Reference 20140330-31-32-33-34, http://www.ccma.cat/tv3/marato/en/ projectes-financats/2013/212/). The group at CIC biomaGUNE also acknowledges MINECO (Spain) for funding through Grant CTQ2017-87637-R. I. Cardoso worked under the Investigator FCT Program which is financed by national funds through the Foundation for Science and Technology (FCT, Portugal) and co-financed by the European Social Fund (ESF) through the Human Potential Operational Programme (HPOP), type 4.2 - Promotion of Scientific Employment.Peer reviewe

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Effects of transthyretin stabilization by wine polyphenols in the modulation of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common type of dementia, accounting for 60% to 80% of all cases worldwide. Senile plaques, one of AD hallmarks, are mainly constituted of A peptide. Transthyretin (TTR) has been described to exert a neuroprotective effect in AD by interacting with A. This activity is dependent on its stability, thus compounds that stabilize TTR tetrameric fold increase TTR/A binding. Most of the compounds identified as TTR stabilizers belong to the group of non-steroid anti inflammatory drugs and compete with thyroxine (T4), the natural TTR stabilizer. Investigate the neuroprotective potential of wine polyphenols (Resveratrol, Catechin, Malvidin and Polyphenolic Extract) by exploring their ability to improve TTR/A interaction.info:eu-repo/semantics/publishedVersio

Insights on the Interaction between Transthyretin and Aβ in Solution. A Saturation Transfer Difference (STD) NMR Analysis of the Role of Iododiflunisal

Herein, key structural features of the interaction between TTR and the Aβ(12−28) peptide (3), the essential recognition element of Aβ, have been unravelled by STD-NMR spectroscopy methods in solution.The group at CIC bioGUNE acknowledges MINECO (Spain) for funding through Grant CTQ2015-64597-C2-1-P and a Juan de la Cierva contract to A.G

Insights on the Interaction between Transthyretin and Aβ in Solution. A Saturation Transfer Difference (STD) NMR Analysis of the Role of Iododiflunisal

Several strategies against Alzheimer disease (AD) are directed to target Aβ-peptides. The ability of transthyretin (TTR) to bind Aβ-peptides and the positive effect exerted by some TTR stabilizers for modulating the TTR–Aβ interaction have been previously studied. Herein, key structural features of the interaction between TTR and the Aβ(12–28) peptide (<b>3</b>), the essential recognition element of Aβ, have been unravelled by STD-NMR spectroscopy methods in solution. Molecular aspects related to the role of the TTR stabilizer iododiflunisal (IDIF, <b>5</b>) on the TTR–Aβ complex have been also examined. The NMR results, assisted by molecular modeling protocols, have provided a structural model for the TTR–Aβ interaction, as well as for the ternary complex formed in the presence of IDIF. This basic structural information could be relevant for providing light on the mechanisms involved in the ameliorating effects of AD symptoms observed in AD/TTR^± animal models after IDIF treatment and eventually for designing new molecules toward AD therapeutic drugs