Serum amyloid A1 is involved in amyloid plaque aggregation and memory decline in amyloid beta abundant condition

Jang, Soyoung; Jang, Woo Young; Choi, Minjee; Lee, Jin‐Hee; Kwon, Wookbong; Yi, Junkoo; Park, Si Jun; Yoon, Duhak; Lee, Sanggyu; Kim, Myoung Ok; Ryoo, Zae Young

doi:10.1007/s11248-019-00166-x

Cited by 19 publications

(26 citation statements)

References 26 publications

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“…It has been recently described that overexpressed liver-derived SAA1 protein in mice accumulates in the brain crossing the BBB, triggering a depressive-like behavior of mice [38]. Moreover, in double transgenic APP/SAA1 mice, SAA1 exacerbated amyloid aggregation, glial activation, causing greater memory decline in APP/SAA1 compared to single transgenic APP mice [39]. Other studies in humans showed that SAA1 was detected in senile plaques in Alzheimer's disease tissue, predominantly localized to neuritic plaques [40].…”

Section: Discussionmentioning

confidence: 99%

Serum Amyloid A1/Toll-Like Receptor-4 Axis, an Important Link between Inflammation and Outcome of TBI Patients

et al. 2021

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Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide without any validated biomarker or set of biomarkers to help the diagnosis and evaluation of the evolution/prognosis of TBI patients. To achieve this aim, a deeper knowledge of the biochemical and pathophysiological processes triggered after the trauma is essential. Here, we identified the serum amyloid A1 protein-Toll-like receptor 4 (SAA1-TLR4) axis as an important link between inflammation and the outcome of TBI patients. Using serum and mRNA from white blood cells (WBC) of TBI patients, we found a positive correlation between serum SAA1 levels and injury severity, as well as with the 6-month outcome of TBI patients. SAA1 levels also correlate with the presence of TLR4 mRNA in WBC. In vitro, we found that SAA1 contributes to inflammation via TLR4 activation that releases inflammatory cytokines, which in turn increases SAA1 levels, establishing a positive proinflammatory loop. In vivo, post-TBI treatment with the TLR4-antagonist TAK242 reduces SAA1 levels, improves neurobehavioral outcome, and prevents blood–brain barrier disruption. Our data support further evaluation of (i) post-TBI treatment in the presence of TLR4 inhibition for limiting TBI-induced damage and (ii) SAA1-TLR4 as a biomarker of injury progression in TBI patients.

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Section: Discussionmentioning

confidence: 99%

Serum Amyloid A1/Toll-Like Receptor-4 Axis, an Important Link between Inflammation and Outcome of TBI Patients

et al. 2021

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“…We demonstrated that the progressive increase in iron content that we observed in animals' brain during aging triggers the onset of an neuroinflammatory condition, measured by an increased expression of SAA-1 (Serum Amyloid protein A1), a protein expressed in acute inflammatory phase and a reliable marker of neuroinflammation (Yu 2019). During acute neuroinflammation, in fact, SAA-1 increases up to 1000 times and can stimulate the release of cytokines and chemokines (Jang 2019). Interestingly, the same protein has been found to be overexpressed in the brain of AD patients, as well as in the AD mouse model APP/SAA, that recapitulates the disease (Jang 2019).…”

Section: Discussionmentioning

confidence: 73%

“…During acute neuroinflammation, in fact, SAA-1 increases up to 1000 times and can stimulate the release of cytokines and chemokines (Jang 2019). Interestingly, the same protein has been found to be overexpressed in the brain of AD patients, as well as in the AD mouse model APP/SAA, that recapitulates the disease (Jang 2019). Moreover, the increase in transcription of Nrf2, a redox-sensitive transcription factor whose activation results in cellular antioxidant responses via modulation of several stress-responsive proteins (Jiang 2019), supports the evidence of an oxidative stressful condition in our WT O mice brain.…”

Section: Discussionmentioning

confidence: 99%

“…To investigate if the accumulation of iron in the brain led to a neuroinflammatory processes and if it could cause oxidative stress, we analysed the two main markers of these biological processes, SAA1 (Jang 2019) and Nrf2 (Jiang 2019) respectively. SAA1 expression levels significantly become more than 20 times higher in WT O animals compared to WT A mice (Fig.…”

Section: Iron-dependent Inflammatory Response and Oxidative Stress During Agingmentioning

confidence: 99%

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BBB damage in aging causes brain iron deposits via astrocyte-neuron crosstalk and Hepc/Fpn1 pathway

Mezzanotte

Boido

et al. 2021

Preprint

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During aging, iron accumulates in brain’s regions vulnerable to neurodegeneration: the cerebral cortex and the hippocampus. However, the mechanism of iron regulation in the brain remains scarce. Here, we demonstrated for the first time the involvement of the Hepcidin/Ferroportin1 pathway in brain iron metabolism during aging.We demonstrated the alteration of BBB integrity, that leads to increased iron permeability and deregulation of iron homeostasis during aging. We found that brain iron overload drives Hepcidin upregulation and, consequently, the inhibition of the iron exporter Ferroportin1, neuroinflammation and oxidative stress. Moreover, both in the cerebral cortex and hippocampus Ferroportin1 colocalizes with astrocytes, while the iron storage protein ferritin light-chain with neurons. This differential distribution suggests that astrocytes mediate iron shuttling and neurons are unable to metabolize it. Furthermore, we observed NCOA4-dependent ferritinophagy of ferritin heavy-chain isoforms determining the increase of light-chain enriched ferritin heteropolymers that are more efficient as iron chelators. Altogether, these data highlight the involvement of the Hepcidin/Ferroportin1 axis and NCOA4 during mice aging as a response to a higher iron influx to the brain.

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“…In fields of regulating inflammation and immunity and lipid metabolism, SAA protein plays an important role that benefits the body [6,11,12]. SAA is an important amyloid precursor and plays a key role in AA amyloidosis which impacts ∼1% of patients with chronic inflammation [13,14]. Furthermore, SAA is a clinically important biomarker for inflammatory diseases [15,16].…”

Section: Introductionmentioning

confidence: 99%

Aggregation of Mouse Serum Amyloid A Protein Was Promoted by Amyloid-Enhancing Factors with the More Genetically Homologous Serum Amyloid A

Lin

Watanabe

Kuragano

et al. 2021

IJMS

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Amyloid A (AA) amyloidosis is a condition in which amyloid fibrils characterized by a linear morphology and a cross-β structure accumulate and are deposited extracellularly in organs, resulting in chronic inflammatory diseases and infections. The incidence of AA amyloidosis is high in humans and several animal species. Serum amyloid A (SAA) is one of the most important precursor amyloid proteins and plays a vital step in AA amyloidosis. Amyloid enhancing factor (AEF) serves as a seed for fibril formation and shortens the onset of AA amyloidosis sharply. In this study, we examined whether AEFs extracted and purified from five animal species (camel, cat, cattle, goat, and mouse) could promote mouse SAA (mSAA) protein aggregation in vitro using quantum-dot (QD) nanoprobes to visualize the aggregation. The results showed that AEFs shortened and promoted mSAA aggregation. In addition, mouse and cat AEFs showed higher mSAA aggregation-promoting activity than the camel, cattle, and goat AEFs. Interestingly, homology analysis of SAA in these five animal species revealed a more similar amino acid sequence homology between mouse and cat than between other animal species. Furthermore, a detailed comparison of amino acid sequences suggested that it was important to mSAA aggregation-promoting activity that the 48th amino acid was a basic residue (Lys) and the 125th amino acid was an acidic residue (Asp or Glu). These data imply that AA amyloidosis exhibits higher transmission activity among animals carrying genetically homologous SAA gene, and may provide a new understanding of the pathogenesis of amyloidosis.

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Serum amyloid A1 is involved in amyloid plaque aggregation and memory decline in amyloid beta abundant condition

Cited by 19 publications

References 26 publications

Serum Amyloid A1/Toll-Like Receptor-4 Axis, an Important Link between Inflammation and Outcome of TBI Patients

Serum Amyloid A1/Toll-Like Receptor-4 Axis, an Important Link between Inflammation and Outcome of TBI Patients

BBB damage in aging causes brain iron deposits via astrocyte-neuron crosstalk and Hepc/Fpn1 pathway

Aggregation of Mouse Serum Amyloid A Protein Was Promoted by Amyloid-Enhancing Factors with the More Genetically Homologous Serum Amyloid A

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