CuII(atsm) Attenuates Neuroinflammation

Choo, Xin Yi; Liddell, Jeffrey R.; Huuskonen, Mikko T; Grubman, Alexandra; Moujalled, Diane; Roberts, Jessica; Kysenius, Kai; Patten, Lauren; Quek, Hazel; Oikari, Lotta E.; Duncan, Clare; James, Simon; McInnes, Lachlan E.; Hayne, David J.; Donnelly, Paul S.; Pollari, Eveliina; Vähätalo, Suvi; Lejavová, Katarína; Kettunen, Mikko I.; Malm, Tarja; Koistinaho, Jari; White, Anthony R.

doi:10.3389/fnins.2018.00668

Cited by 30 publications

(46 citation statements)

References 97 publications

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“…We have previously shown that the LPS treatment of primary astrocytes increases the secretion of IL6 and MCP-1. ( 29 ) The elevated levels of these cytokines have also been measured from AD patients. ( 30 , 31 ) The effect of LPS and AD transgenes on Lat1 mRNA expression was investigated by qRT PCR and protein expression was investigated by quantitative LC-MS/MS based proteomics.…”

Section: Resultsmentioning

confidence: 99%

Alzheimer’s Disease Phenotype or Inflammatory Insult Does Not Alter Function of L-Type Amino Acid Transporter 1 in Mouse Blood-Brain Barrier and Primary Astrocytes

et al. 2018

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PurposeThe study aim was to evaluate the effect of Alzheimer’s disease (AD) and inflammatory insult on the function of L-type amino acid transporter 1 (Lat1) at the mouse blood-brain barrier (BBB) as well as Lat1 function and expression in mouse primary astrocytes.MethodsThe Lat1 function and expression was determined in wildtype astrocytes with and without lipopolysaccharide (LPS)-induced inflammation and in LPS treated AD APP/PS1 transgenic astrocytes. The function of Lat1 at the BBB was evaluated in wildtype mice with and without LPS-induced neuroinflammation and APP/PS1 transgenic mice by in situ brain perfusion.ResultsThere were 2.1 and 1.6 -fold decreases in Lat1 mRNA and protein expression in LPS-treated wildtype astrocytes compared to vehicle-treated astrocytes. In contrast, Lat1 mRNA and protein expression were increased by 1.7 and 1.2 -fold (not statistically significant) in the transgenic cells. A similar trend was observed in the cell uptake of [14C]-L-leucine. There were no statistically significant differences in [14C]-L-leucine BBB permeation between the groups.ConclusionsThe results showed that neither LPS-induced inflammation or the presence of APP/PS1 mutations alters Lat1 function at the mouse BBB as well as Lat1 protein expression and function in mouse primary astrocytes.

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Section: Resultsmentioning

confidence: 99%

Alzheimer’s Disease Phenotype or Inflammatory Insult Does Not Alter Function of L-Type Amino Acid Transporter 1 in Mouse Blood-Brain Barrier and Primary Astrocytes

et al. 2018

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“…Furthermore, there is evidence that the immunomodulatory potential of systemic copper bis(thiosemicarbazones), which are stable, lipophilic neutral Cu 2+ complexes that are capable of crossing cell membranes and the blood-brain barrier. This compound can inhibit microglial and astrocytic activation, and reducing the acute cerebrovascular inflammation caused by bacterial lipopolysaccharide [130] . Based on the evidence above, it would be expected that increasing copper levels in the body would restore its homeostasis in the brain.…”

Section: Copper (Cu)mentioning

confidence: 99%

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation

Huat

Camats-Perna

Newcombe

et al. 2019

Journal of Molecular Biology

359

180

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As the median age of the population increases, the number of individuals with Alzheimer's disease (AD) and the associated socioeconomic burden are predicted to worsen. While aging and inherent genetic predisposition play major roles in the onset of AD, lifestyle, physical fitness, medical condition, and social environment have emerged as relevant disease modifiers. These environmental risk factors can play a key role in accelerating or decelerating disease onset and progression. Among known environmental risk factors, chronic exposure to various metals has become more common among the public as the aggressive pace of anthropogenic activities releases excess amount of metals into the environment. As a result, we are exposed not only to essential metals, such as iron, copper, zinc and manganese, but also to toxic metals including lead, aluminum, and cadmium, which perturb metal homeostasis at the cellular and organismal levels. Herein, we review how these metals affect brain physiology and immunity, as well as their roles in the accumulation of toxic AD proteinaceous species (i.e., β-amyloid and tau). We also discuss studies that validate the disruption of immune-related pathways as an important mechanism of toxicity by which metals can contribute to AD. Our goal is to increase the awareness of metals as players in the onset and progression of AD.

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“…There is proof of the bis(thiosemicarbazone) copper(II) complex having the immunomodulatory potential [ 276 , 277 ], and greater BBB permeability. It inhibits microglial as well as astrocytic inflammatory responses and also has a role in the decrement of bacterial lipopolysaccharide (LPS) induced inflammation [ 278 ]. Some researchers have suggested that excess dietary Cu intake increases AD risks, and diets with measured copper should be supported.…”

Section: Therapeutics To Tackle Copper Ions In Admentioning

confidence: 99%

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Ejaz

Wang

Lang

2020

IJMS

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Alzheimer’s disease (AD) is an irreversible, age-related progressive neurological disorder, and the most common type of dementia in aged people. Neuropathological lesions of AD are neurofibrillary tangles (NFTs), and senile plaques comprise the accumulated amyloid-beta (Aβ), loaded with metal ions including Cu, Fe, or Zn. Some reports have identified metal dyshomeostasis as a neurotoxic factor of AD, among which Cu ions seem to be a central cationic metal in the formation of plaque and soluble oligomers, and have an essential role in the AD pathology. Cu-Aβ complex catalyzes the generation of reactive oxygen species (ROS) and results in oxidative damage. Several studies have indicated that oxidative stress plays a crucial role in the pathogenesis of AD. The connection of copper levels in AD is still ambiguous, as some researches indicate a Cu deficiency, while others show its higher content in AD, and therefore there is a need to increase and decrease its levels in animal models, respectively, to study which one is the cause. For more than twenty years, many in vitro studies have been devoted to identifying metals’ roles in Aβ accumulation, oxidative damage, and neurotoxicity. Towards the end, a short review of the modern therapeutic approach in chelation therapy, with the main focus on Cu ions, is discussed. Despite the lack of strong proofs of clinical advantage so far, the conjecture that using a therapeutic metal chelator is an effective strategy for AD remains popular. However, some recent reports of genetic-regulating copper transporters in AD models have shed light on treating this refractory disease. This review aims to succinctly present a better understanding of Cu ions’ current status in several AD features, and some conflicting reports are present herein.

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CuII(atsm) Attenuates Neuroinflammation

Cited by 30 publications

References 97 publications

Alzheimer’s Disease Phenotype or Inflammatory Insult Does Not Alter Function of L-Type Amino Acid Transporter 1 in Mouse Blood-Brain Barrier and Primary Astrocytes

Alzheimer’s Disease Phenotype or Inflammatory Insult Does Not Alter Function of L-Type Amino Acid Transporter 1 in Mouse Blood-Brain Barrier and Primary Astrocytes

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

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