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Serum Amyloid A is Expressed in the Brain After Traumatic Brain Injury in a Sex-Dependent Manner.

ABSTRACT: Serum amyloid A (SAA) is an acute phase protein upregulated in the liver after traumatic brain injury (TBI). So far, it has not been investigated whether SAA expression also occurs in the brain in response to TBI. For this, we performed a moderate controlled cortical impact injury in adult male and female mice and analyzed brain, blood, and liver samples at 6 h, 1, 3, and 10 days post-injury (dpi). We measured the levels of SAA in serum, brain and liver by western blot. We also used immunohistochemical techniques combined with in situ hybridization to determine SAA mRNA and protein expression in the brain. Our results revealed higher levels of SAA in the bloodstream in males compared to females at 6 h post-TBI. Liver and serum SAA protein showed a peak of expression at 1 dpi followed by a decrease at 3 to 10 dpi in both sexes. Both SAA mRNA and protein expression colocalize with astrocytes and macrophages/microglia in the cortex, corpus callosum, thalamus, and hippocampus after TBI. For the first time, here we show that SAA is expressed in the brain in response to TBI. Collectively, SAA expression was higher in males compared to females, and in association with the sex-dependent neuroinflammatory response after brain injury. We suggest that SAA could be a crucial protein associated to the acute neuroinflammation following TBI, not only for its hepatic upregulation but also for its expression in the injured brain.

SUBMITTER: Soriano S

PROVIDER: S-EPMC7426254 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mild traumatic brain injury (mTBI) is an important public health issue, as it can lead to long-term neurological symptoms and risk of neurodegenerative disease. The pathophysiological mechanisms driving this remain unclear, and currently there are no effective therapies for mTBI. In this study on repeated mTBI (rmTBI), we have induced three mild closed-skull injuries or sham procedures, separated by 24 h, in C57BL/6 mice. We show that rmTBI mice have prolonged righting reflexes and astrogliosis, with neurological impairment in the Morris water maze (MWM) and the light dark test. Cortical and hippocampal tissue analysis revealed DNA damage in the form of double-strand breaks, oxidative damage, and R-loops, markers of cellular senescence including p16 and p21, and signaling mediated by the cGAS-STING pathway. This study identified novel sex differences after rmTBI in mice. Although these markers were all increased by rmTBI in both sexes, females had higher levels of DNA damage, lower levels of the senescence protein p16, and lower levels of cGAS-STING signaling proteins compared to their male counterparts. Single-cell RNA sequencing of the male rmTBI mouse brain revealed activation of the DNA damage response, evidence of cellular senescence, and pro-inflammatory markers reminiscent of the senescence-associated secretory phenotype (SASP) in neurons and glial cells. Cell-type specific changes were also present with evidence of brain immune activation, neurotransmission alterations in both excitatory and inhibitory neurons, and vascular dysfunction. Treatment of injured mice with the senolytic drug ABT263 significantly reduced markers of senescence only in males, but was not therapeutic in females. The reduction of senescence by ABT263 in male mice was accompanied by significantly improved performance in the MWM. This study provides compelling evidence that senescence contributes to brain dysfunction after rmTBI, but may do so in a sex-dependent manner.

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Serum Amyloid A is Expressed in the Brain After Traumatic Brain Injury in a Sex-Dependent Manner.

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