Overexpression of serum amyloid a 1 induces depressive-like behavior in mice

Jang, Woo Young; Lee, Boram; Jeong, Jin Woo; Sung, Young Kwan; Choi, Minjee; Park, Song; Kim, Hyerim; Jang, Soyoung; Kim, Hyunmin; Joo, Kyungil; Lee, Jeong-Woong; Choo, Yeon‐Sik; Kim, Eun-Joo; Ryoo, Zae Young

doi:10.1016/j.brainres.2016.09.003

Cited by 26 publications

(28 citation statements)

References 43 publications

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“…A-SAA deposits occur in neurovasculature and brain microinfarcts of hypertensive primates (45), in the brain parenchyma and neurovasculature of SAA1-overexpressing transgenic mice after LPS treatment (46), in circumventricular organs and the choroid plexus in systemic amyloid A amyloidosis (47), and in myelin sheaths of patients with multiple sclerosis (43). It has recently been found that hepatic overexpression of A-SAA induced detectable levels of liver-derived A-SAA in the CNS, neurovascular pathologies, and depression-like symptoms in aged mice (48); however, it remains unknown how liver-derived SAA can enter the CNS or whether liver-derived SAA can enter the CNS after O 3 exposure.…”

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confidence: 99%

Serum amyloid A: an ozone‐induced circulating factor with potentially important functions in the lung‐brain axis

et al. 2017

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Accumulating evidence suggests that O 3 exposure may contribute to CNS dysfunction. Here, we posit that inflammatory and acute-phase proteins in the circulation increase after O 3 exposure and systemically convey signals of O 3 exposure to the CNS. To model acute O 3 exposure, female Balb/c mice were exposed to 3 ppm O 3 or forced air for 2 h and were studied after 6 or 24 h. Of 23 cytokines and chemokines, only KC/CXCL1 was increased in blood 6 h after O 3 exposure. The acute-phase protein serum amyloid A (A-SAA) was significantly increased by 24 h, whereas C-reactive protein was unchanged. A-SAA in blood correlated with total leukocytes, macrophages, and neutrophils in bronchoalveolar lavage from O 3 -exposed mice. A-SAA mRNA and protein were increased in the liver. We found that both isoforms of A-SAA completely crossed the intact blood-brain barrier, although the rate of SAA2.1 influx was approximately 5 times faster than that of SAA1.1. Finally, A-SAA protein, but not mRNA, was increased in the CNS 24 h post-O 3 exposure. Our findings suggest that A-SAA is functionally linked to pulmonary inflammation in our O 3 exposure model and that A-SAA could be an important systemic signal of O 3 exposure to the CNS.-Erickson,

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confidence: 99%

Serum amyloid A: an ozone‐induced circulating factor with potentially important functions in the lung‐brain axis

et al. 2017

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“…Because amyloid β-peptide binds to large CSF-HDL but not to apoE the authors postulated that inflammation in the CNS may impair amyloid clearance due to loss of apoE from CSF-HDL. Intriguingly, over-expression of SAA1 induces depressive-like behaviour in mice 72 . As SAA contains a cholesterol binding site near its amino terminus it is likely to have a high affinity for cholesterol-rich myelin.…”

Section: Discussionmentioning

confidence: 99%

Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A

Barbierato

Borri

Facci

et al. 2017

Sci Rep

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Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer’s disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-α and lipopolysaccaride (LPS). TNF-α time-dependently increased Saa1 (but not Saa3) mRNA expression in purified microglia, enriched astrocytes, and OPCs (as did LPS for microglia and astrocytes). Astrocytes depleted of microglia were markedly less responsive to TNF-α and LPS, even after re-addition of microglia. Microglia and enriched astrocytes showed complementary Saa1 expression profiles following TNF-α or LPS challenge, being higher in microglia with TNF-α and higher in astrocytes with LPS. Recombinant human apo-SAA stimulated production of both inflammatory mediators and its own mRNA in microglia and enriched, but not microglia-depleted astrocytes. Co-ultramicronized palmitoylethanolamide/luteolin, an established anti-inflammatory/ neuroprotective agent, reduced Saa1 expression in OPCs subjected to TNF-α treatment. These last data, together with past findings suggest that co-ultramicronized palmitoylethanolamide/luteolin may be a novel approach in the treatment of inflammatory demyelinating disorders like MS.

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“…The acute SAA isoforms have been shown to readily cross the intact BBB, where radiolabelled SAA traversed the endothelial barrier to enter the brain parenchyma [ 15 ]. In a recent study, a liver-specific SAA over-expressing transgenic mouse model was used to evaluate whether acute circulating SAA can contribute to neurodegenerative disorders [ 26 ]. Excessive production of SAA in this transgenic model resulted in accumulation of SAA in the brain, and this stimulated an increase in microglial cell numbers and expression of pro-inflammatory cytokines including IL-6 and TNFα [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study, a liver-specific SAA over-expressing transgenic mouse model was used to evaluate whether acute circulating SAA can contribute to neurodegenerative disorders [ 26 ]. Excessive production of SAA in this transgenic model resulted in accumulation of SAA in the brain, and this stimulated an increase in microglial cell numbers and expression of pro-inflammatory cytokines including IL-6 and TNFα [ 26 ]. In addition, chronic elevation of circulating SAA resulted in behavioural abnormalities that are indicative of depressive-like behaviour and social withdrawal [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Excessive production of SAA in this transgenic model resulted in accumulation of SAA in the brain, and this stimulated an increase in microglial cell numbers and expression of pro-inflammatory cytokines including IL-6 and TNFα [ 26 ]. In addition, chronic elevation of circulating SAA resulted in behavioural abnormalities that are indicative of depressive-like behaviour and social withdrawal [ 26 ]. Importantly, our study provides a clinically relevant infectious model of excessive peripheral SAA production that leads to microglial pro-inflammatory activity and neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

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Increased hypothalamic microglial activation after viral-induced pneumococcal lung infection is associated with excess serum amyloid A production

Wang

Blackall

Sominsky

et al. 2018

J Neuroinflammation

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BackgroundIt is well established that lung pathology and inflammation are more severe during respiratory infections complicated by the presence of both bacteria and viruses. Whilst co-infection can result in invasive pneumococcal disease and systemic inflammation, the neuroinflammatory consequences of co-infection are poorly characterised.MethodsIn this study, we utilised a mouse co-infection model involving Streptococcus pneumoniae (S. pneumoniae) and influenza A virus (IAV) lung infection, and we also isolated microglia for ex vivo stimulation with pneumococcus or serum amyloid A (SAA).ResultsCo-infection but not S. pneumoniae or IAV alone significantly increased the number of amoeboid-shaped microglia and expression of pro-inflammatory cytokines including tumour necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and C-C motif chemokine ligand-2 (CCL-2) in the hypothalamus. Pneumococcus was only detected in the hypothalamus of co-infected mice. In addition, the systemic inflammatory cytokines TNFα, IL-1β and IL-6 were not elevated in co-infected mice relative to IAV-infected mice, whereas SAA levels were markedly increased in co-infected mice (p < 0.05). SAA and its functional receptor termed formyl peptide receptor 2 (Fpr2) transcript expression were also increased in the hypothalamus. In mouse primary microglia, recombinant SAA but not S. pneumoniae stimulated TNFα, IL-1β, IL-6 and CCL-2 expression, and this response was completely blocked by the pro-resolving Fpr2 agonist aspirin-triggered resolvin D1 (AT-RvD1).ConclusionsIn summary, lung co-infection increased the number of ‘activated’ amoeboid-shaped microglia and inflammatory cytokine expression in the hypothalamus. Whilst persistent pneumococcal brain infection was observed, SAA proved to be a much more potent stimulus of microglia than pneumococci, and this response was potently suppressed by the anti-inflammatory AT-RvD1. Targeting Fpr2 with pro-resolving eicosanoids such as AT-RvD1 may restore microglial homeostasis during severe respiratory infections.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1234-1) contains supplementary material, which is available to authorized users.

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Overexpression of serum amyloid a 1 induces depressive-like behavior in mice

Cited by 26 publications

References 43 publications

Serum amyloid A: an ozone‐induced circulating factor with potentially important functions in the lung‐brain axis

Serum amyloid A: an ozone‐induced circulating factor with potentially important functions in the lung‐brain axis

Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A

Increased hypothalamic microglial activation after viral-induced pneumococcal lung infection is associated with excess serum amyloid A production

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