Peripherally misfolded proteins exacerbate ischemic stroke-induced neuroinflammation and brain injury

Abstract

Background Protein aggregates can be found in peripheral organs, such as the heart, kidney, and pancreas, but little is known about the impact of peripherally misfolded proteins on neuroinflammation and brain functional recovery following ischemic stroke. Methods Here, we studied the ischemia/reperfusion (I/R) induced brain injury in mice with cardiomyocyte-restricted overexpression of a missense (R120G) mutant small heat shock protein, αB-crystallin (CryABR120G), by examining neuroinflammation and brain functional recovery following I/R in comparison to their non-transgenic (Ntg) littermates. To understand how peripherally misfolded proteins influence brain functionality, exosomes were isolated from CryABR120G and Ntg mouse blood and were used to treat wild-type (WT) mice and primary cortical neuron-glia mix cultures. Additionally, isolated protein aggregates from the brain following I/R were isolated and subjected to mass-spectrometric analysis to assess whether the aggregates contained the mutant protein, CryABR120G. To determine whether the CryABR120G misfolding can self-propagate, a misfolded protein seeding assay was performed in cell cultures. Results Our results showed that CryABR120G mice exhibited dramatically increased infarct volume, delayed brain functional recovery, and enhanced neuroinflammation and protein aggregation in the brain following I/R when compared to the Ntg mice. Intriguingly, mass-spectrometric analysis of the protein aggregates isolated from CryABR120G mouse brains confirmed presence of the mutant CryABR120G protein in the brain. Importantly, intravenous administration of WT mice with the exosomes isolated from CryABR120G mouse blood exacerbated I/R-induced cerebral injury in WT mice. Moreover, incubation of the CryABR120G mouse exosomes with primary neuronal cultures induced pronounced protein aggregation. Transduction of CryABR120G aggregate seeds into cell cultures caused normal CryAB proteins to undergo dramatic aggregation and form large aggregates, suggesting self-propagation of CryABR120G misfolding in cells. Conclusions These results suggest that peripherally misfolded proteins in the heart remotely enhance neuroinflammation and exacerbate brain injury following I/R likely through exosomes, which may represent an underappreciated mechanism underlying heart-brain crosstalk.

Impact of Cardiovascular Diseases on Ischemic Stroke Outcomes

“…2 ). These findings further highlight a significant role of the heart on brain functional recovery following stroke [ 47 ].…”

“…A recent study from our group highlights the important effect of aberrant protein aggregation in the cardiac muscle on ischemic stroke-caused brain injury and functional recovery in mice. Specifically, mice with cardiomyocyte-restricted transgenic expression of a missense (R120G) mutant alpha B-crystallin (CryAB R120G ) exhibit significantly increased glial activation, infarct volume, impaired functional recovery, learning and memory deficits, and increased neuroinflammation following surgically induced cerebral ischemia/reperfusion [ 47 ].…”

The involvement of small heat shock protein in chemoresistance in ovarian cancer - in vitro study

“…Only in the A2780 WT cell line, we were able to observe their small amount (HSPB5 and HSPB6). A few animal models have shown that secretion of small HSPs via exosomal cargo in pathophysiological events such as ischemic stroke or myocardial infarction has huge implications on their recovery (Liu et al, 2021[ 35 ]; Yu et al, 2019[ 64 ]). However, there is limited data about their involvement in malignant progression.…”

Allicin, an Antioxidant and Neuroprotective Agent, Ameliorates Cognitive Impairment

“…Therefore, the mitochondrial dysfunction is mostly associated with the pathogenesis of neurological conditions [ 94 , 95 , 96 , 97 , 98 ]. The causes for the neurological diseases also include deleterious mitochondrial DNA [ 99 ], accumulated misfolded proteins [ 100 ], problems in the calcium influx [ 101 ], flaws in the mitochondrial oxidative phosphorylation systems (OXPHOS) [ 102 ], elevated levels of ROS [ 103 ], and apoptosis of neuron cells [ 104 ]. After the cellular death, released DNA, proteins and cellular debris promote microglia, initiate inflammation and damage the tissue [ 95 ].…”