Cerebrospinal Fluid Proteins as Regulators of Beta‐amyloid Aggregation and Toxicity

Pate, Kayla M.; Murphy, Regina M.

doi:10.1002/ijch.201600078

Cited by 19 publications

(16 citation statements)

References 132 publications

(175 reference statements)

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“…Amyloid plaques or senile plaques mostly consist of the Aβ peptides, the essential peptide whose presence at a nanomolar concentration is shown by numerous studies in the cerebrospinal fluid (CSF) as well as in serum [ 119 , 120 ]. However, the TASTPM animal model study pointed out that the concentration of Cu in the Alzheimer’s brain does not link to plaques deposition [ 121 ].…”

Section: Copper Ion Implication 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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Section: Copper Ion Implication 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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“…TTR, a 55 kDa homotetramer 14 with a dimer of dimers quaternary structure, is a protein present in the serum and cerebrospinal fluid 15 (CSF) that carries retinol and the thyroid hormone thyroxine (T4) 16 . The stability of the tetrameric form of TTR plays a pivotal role in the amyloidogenic properties of the native protein and its mutants 17,18 , which are in the cause of a series of severe amyloid diseases, i.e.…”

Section: Introductionmentioning

confidence: 99%

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

Rios

Gómez‐Vallejo

Martín

et al. 2019

Sci Rep

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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.

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“…Cystatin C, a biomarker of renal function (Grubb et al ), is a small (13.3‐kDa) basic protein expressed by all nucleated cells. Notably, cystatin C is more abundant in the central nervous system, especially in the cerebrospinal fluid and brain tissues (Turk et al ; Pate and Murphy ). Recent studies have demonstrated that the expression of cystatin C is increased in stroke (Xiao et al ; Yang et al ) and that this increase seems to be a compensatory response that has a protective effect against ischemic brain injury (Ni et al ; D'Adamio ; Yang et al ).…”

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confidence: 99%

Cystatin C improves blood–brain barrier integrity after ischemic brain injury in mice

Yang

Chang

et al. 2019

Journal of Neurochemistry

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Cystatin C, a well-established biomarker of renal function, has been associated with a protective effect against stroke. However, the potential neuroprotective mechanism of cystatin C in ischemic brain injury remains unclear. Our study hypothesized that cystatin C can ameliorate blood-brain barrier (BBB) disruption by up-regulating caveolin-1 expression, thereby improving neurological outcomes in cerebral ischemic injury. Western blotting, immunohistochemistry, immunofluorescence staining, and immunoprecipitation were performed to investigate target proteins. Evans Blue and gelatin zymography were used to examine the effect of cystatin C on BBB disruption. Plasmid and small interfering RNA transfection was used to observe alterations in caveolin-1 and occludin expression induced by changes in cystatin C expression. Intriguingly, our study showed that the expression of both cystatin C and caveolin-1 was increased in middle cerebral artery occlusion-injured mice, and pretreatment with exogenous cystatin C significantly increased caveolin-1 expression, reduced Evans Blue leakage in the injured brain region, and decreased the enzymatic activity of matrix metallopeptidase-9. Meanwhile, our study also showed that the over-expression of cystatin C greatly enhanced caveolin-1 expression, which later increased occludin expression in oxygen-glucose deprivation-exposed brain microvascular endothelial cells. The knockdown of cystatin C induced the opposite outcomes. These experimental results indicate a positive role for cystatin C in the regulation of caveolin-1 and occludin expression in cerebral ischemic injury. Taken together, these data unveil a new mechanism of the regulation of caveolin-1 expression by cystatin C in the maintenance of BBB integrity after ischemic brain injury and provide new clues for the identification of potential therapeutic strategies for stroke. Keywords: bEnd.3, blood-brain barrier, caveolin-1, cystatin C, ischemic brain injury, occludin. are co-first authors.Abbreviations used: BBB, blood-brain barrier; bEnd.3, brain microvascular endothelial; DMEM, Dulbecco's modified Eagle medium; I/R, ischemia/reperfusion; ICV, intracerebroventricular; MCAO, middle cerebral artery occlusion; MMP-9, matrix metallopeptidase-9; MMPs, matrix metalloproteinases; OGD, oxygen-glucose deprivation; PBS, phosphate buffered saline; SDS, sodium dodecyl sulfate; siRNA, small interfering RNA. | 2020 | 153 | 413-425 JOURNAL OF NEUROCHEMISTRY

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Cerebrospinal Fluid Proteins as Regulators of Beta‐amyloid Aggregation and Toxicity

Cited by 19 publications

References 132 publications

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

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

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

Cystatin C improves blood–brain barrier integrity after ischemic brain injury in mice

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