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This review proposes that lipopolysaccharide (LPS, found in the wall of all Gram-negative bacteria) could play a role in causing sporadic Alzheimer's disease (AD). This is based in part upon recent studies showing that: Gram-negative bacteria can form extracellular amyloid; bacterial-encoded 16S rRNA is present in all human brains with over 70% being Gram-negative bacteria; ultrastructural analyses have shown microbes in erythrocytes of AD patients; blood LPS levels in AD patients are 3-fold the levels in control; LPS combined with focal cerebral ischemia and hypoxia produced amyloid-like plaques and myelin injury in adult rat cortex. Moreover, Gram-negative bacterial LPS was found in aging control and AD brains, though LPS levels were much higher in AD brains. In addition, LPS co-localized with amyloid plaques, peri-vascular amyloid, neurons, and oligodendrocytes in AD brains. Based upon the postulate LPS caused oligodendrocyte injury, degraded Myelin Basic Protein (dMBP) levels were found to be much higher in AD compared to control brains. Immunofluorescence showed that the dMBP co-localized with β amyloid (Aβ) and LPS in amyloid plaques in AD brain, and dMBP and other myelin molecules were found in the walls of vesicles in periventricular White Matter (WM). These data led to the hypothesis that LPS acts on leukocyte and microglial TLR4-CD14/TLR2 receptors to produce NFkB mediated increases of cytokines which increase Aβ levels, damage oligodendrocytes and produce myelin injury found in AD brain. Since Aβ is also an agonist for TLR4 receptors, this could produce a vicious cycle that accounts for the relentless progression of AD. Thus, LPS, the TLR4 receptor complex, and Gram-negative bacteria might be treatment or prevention targets for sporadic AD.

Soil management practices, such as tillage method or straw return, could alter soil organic carbon (C) contents. However, the effects of tillage method or straw return on soil organic C (SOC) have showed inconsistent results in different soil/climate/cropping systems. The Yangtze River Delta of China is the main production region of rice and wheat, and rice-wheat rotation is the most important cropping system in this region. However, few studies in this region have been conducted to assess the effects of different tillage methods combined with straw return on soil labile C fractions in the rice-wheat rotation system. In this study, a field experiment was used to evaluate the effects of different tillage methods, straw return and their interaction on soil total organic C (TOC) and labile organic C fractions at three soil depths (0-7, 7-14 and 14-21 cm) for a rice-wheat rotation in Yangzhong of the Yangtze River Delta of China. Soil TOC, easily oxidizable C (EOC), dissolved organic C (DOC) and microbial biomass C (MBC) contents were measured in this study. Soil TOC and labile organic C fractions contents were significantly affected by straw returns, and were higher under straw return treatments than non-straw return at three depths. At 0-7 cm depth, soil MBC was significantly higher under plowing tillage than rotary tillage, but EOC was just opposite. Rotary tillage had significantly higher soil TOC than plowing tillage at 7-14 cm depth. However, at 14-21 cm depth, TOC, DOC and MBC were significantly higher under plowing tillage than rotary tillage except for EOC. Consequently, under short-term condition, rice and wheat straw both return in rice-wheat rotation system could increase SOC content and improve soil quality in the Yangtze River Delta.

Neutrophils have key roles in ischemic brain injury, thrombosis, and atherosclerosis. As such, neutrophils are of great interest as targets to treat and prevent ischemic stroke. After stroke, neutrophils respond rapidly promoting blood–brain barrier disruption, cerebral edema, and brain injury. A surge of neutrophil-derived reactive oxygen species, proteases, and cytokines are released as neutrophils interact with cerebral endothelium. Neutrophils also are linked to the major processes that cause ischemic stroke, thrombosis, and atherosclerosis. Thrombosis is promoted through interactions with platelets, clotting factors, and release of prothrombotic molecules. In atherosclerosis, neutrophils promote plaque formation and rupture by generating oxidized-low density lipoprotein, enhancing monocyte infiltration, and degrading the fibrous cap. In experimental studies targeting neutrophils can improve stroke. However, early human studies have been met with challenges, and suggest that selective targeting of neutrophils may be required. Several properties of neutrophil are beneficial and thus may important to preserve in patients with stroke including antimicrobial, antiinflammatory, and neuroprotective functions.

We aimed to determine if plasma levels of bacterial lipopolysaccharide (LPS) and lipoteichoic acid (LTA) are associated with different causes of stroke and correlate with C-reactive protein (CRP), LPS-binding protein (LBP), and the NIH stroke scale (NIHSS). Ischemic stroke (cardioembolic (CE), large artery atherosclerosis (LAA), small vessel occlusion (SVO)), intracerebral hemorrhage (ICH), transient ischemic attack (TIA) and control subjects were compared (n = 205). Plasma LPS, LTA, CRP, and LBP levels were quantified by ELISA. LPS and CRP levels were elevated in ischemic strokes (CE, LAA, SVO) and ICH compared to controls. LBP levels were elevated in ischemic strokes (CE, LAA) and ICH. LTA levels were increased in SVO stroke compared to TIA but not controls. LPS levels correlated with CRP and LBP levels in stroke and TIA. LPS, LBP and CRP levels positively correlated with the NIHSS and WBC count but negatively correlated with total cholesterol. Plasma LPS and LBP associate with major causes of ischemic stroke and with ICH, whereas LPS/LBP do not associate with TIAs. LTA only associated with SVO stroke. LPS positively correlated with CRP, LBP, and WBC but negatively correlated with cholesterol. Higher LPS levels were associated with worse stroke outcomes.

Hemorrhagic transformation (HT) is a common complication of ischemic stroke that is exacerbated by thrombolytic therapy. Methods to better prevent, predict, and treat HT are needed. In this review, we summarize studies of HT in both animals and humans. We propose that early HT (<18 to 24 hours after stroke onset) relates to leukocyte-derived matrix metalloproteinase-9 (MMP-9) and brain-derived MMP-2 that damage the neurovascular unit and promote blood–brain barrier (BBB) disruption. This contrasts to delayed HT (>18 to 24 hours after stroke) that relates to ischemia activation of brain proteases (MMP-2, MMP-3, MMP-9, and endogenous tissue plasminogen activator), neuroinflammation, and factors that promote vascular remodeling (vascular endothelial growth factor and high-moblity-group-box-1). Processes that mediate BBB repair and reduce HT risk are discussed, including transforming growth factor beta signaling in monocytes, Src kinase signaling, MMP inhibitors, and inhibitors of reactive oxygen species. Finally, clinical features associated with HT in patients with stroke are reviewed, including approaches to predict HT by clinical factors, brain imaging, and blood biomarkers. Though remarkable advances in our understanding of HT have been made, additional efforts are needed to translate these discoveries to the clinic and reduce the impact of HT on patients with ischemic stroke.

microRNA (miRNA) are important regulators of gene expression. In patients with ischemic stroke we have previously shown that differences in immune cell gene expression are present. In this study we sought to determine the miRNA that are differentially expressed in peripheral blood cells of patients with acute ischemic stroke and thus may regulate immune cell gene expression. miRNA from peripheral blood cells of forty-eight patients with ischemic stroke and vascular risk factor controls were compared. Differentially expressed miRNA in patients with ischemic stroke were determined by microarray with qRT-PCR confirmation. The gene targets and pathways associated with ischemic stroke that may be regulated by the identified miRNA were characterized. In patients with acute ischemic stroke, miR-122, miR-148a, let-7i, miR-19a, miR-320d, miR-4429 were decreased and miR-363, miR-487b were increased compared to vascular risk factor controls. These miRNA are predicted to regulate several genes in pathways previously identified by gene expression analyses, including toll-like receptor signaling, NF-κβ signaling, leukocyte extravasation signaling, and the prothrombin activation pathway. Several miRNA are differentially expressed in blood cells of patients with acute ischemic stroke. These miRNA may regulate leukocyte gene expression in ischemic stroke including pathways involved in immune activation, leukocyte extravasation and thrombosis.

MicroRNAs (miRNAs) regulate gene expression and have a critical role in many biologic and pathologic processes. We hypothesized that miRNA expression profiles in injured brain (hippocampus) would show common as well as unique profiles when compared with those of blood. Adult, untouched, control rats were compared with rats with sham surgeries, ischemic strokes, brain hemorrhage (lysed blood, fresh blood, or thrombin), and kainate-induced seizures. Brain and whole-blood miRNA expression profiles were assessed 24 h later using TaqMan rodent miRNA arrays. MicroRNA response profiles were different for each condition. Many miRNAs changed more than 1.5-fold in brain and blood after each experimental manipulation, and several miRNAs were upregulated or downregulated in both brain and blood after a given injury. A few miRNAs (e.g., miR-298, miR-155, and miR-362-3p) were upregulated or downregulated more than twofold in both brain and blood after several different injuries. The results show the possible use of blood miRNAs as biomarkers for brain injury; that selected blood miRNAs may correlate with miRNA changes in the brain; and that many of the mRNAs, previously shown to be regulated in brain and blood after brain injury, are likely accounted for by changes in miRNA expression.

Background After ischemic stroke (IS), peripheral leukocytes infiltrate the damaged region and modulate the response to injury. Peripheral blood cells display distinctive gene expression signatures post-IS and these transcriptional programs reflect changes in immune responses to IS. Dissecting the temporal dynamics of gene expression after IS improves our understanding of immune and clotting responses at the molecular and cellular level that are involved in acute brain injury and may assist with time-targeted, cell-specific therapy. Methods The transcriptomic profiles from peripheral monocytes, neutrophils, and whole blood from 38 ischemic stroke patients and 18 controls were analyzed with RNA-seq as a function of time and etiology after stroke. Differential expression analyses were performed at 0–24 h, 24–48 h, and >48 h following stroke. Results Unique patterns of temporal gene expression and pathways were distinguished for monocytes, neutrophils, and whole blood with enrichment of interleukin signaling pathways for different time points and stroke etiologies. Compared to control subjects, gene expression was generally upregulated in neutrophils and generally downregulated in monocytes over all times for cardioembolic, large vessel, and small vessel strokes. Self-organizing maps identified gene clusters with similar trajectories of gene expression over time for different stroke causes and sample types. Weighted Gene Co-expression Network Analyses identified modules of co-expressed genes that significantly varied with time after stroke and included hub genes of immunoglobulin genes in whole blood. Conclusions Altogether, the identified genes and pathways are critical for understanding how the immune and clotting systems change over time after stroke. This study identifies potential time- and cell-specific biomarkers and treatment targets.

We postulate that myelin injury contributes to cholesterol release from myelin and cholesterol dysmetabolism which contributes to Abeta dysmetabolism, and combined with genetic and AD risk factors, leads to increased Abeta and amyloid plaques. Increased Abeta damages myelin to form a vicious injury cycle. Thus, white matter injury, cholesterol dysmetabolism and Abeta dysmetabolism interact to produce or worsen AD neuropathology. The amyloid cascade is the leading hypothesis for the cause of Alzheimer’s disease (AD). The failure of clinical trials based on this hypothesis has raised other possibilities. Even with a possible new success (Lecanemab), it is not clear whether this is a cause or a result of the disease. With the discovery in 1993 that the apolipoprotein E type 4 allele (APOE4) was the major risk factor for sporadic, late-onset AD (LOAD), there has been increasing interest in cholesterol in AD since APOE is a major cholesterol transporter. Recent studies show that cholesterol metabolism is intricately involved with Abeta (Aβ)/amyloid transport and metabolism, with cholesterol down-regulating the Aβ LRP1 transporter and upregulating the Aβ RAGE receptor, both of which would increase brain Aβ. Moreover, manipulating cholesterol transport and metabolism in rodent AD models can ameliorate pathology and cognitive deficits, or worsen them depending upon the manipulation. Though white matter (WM) injury has been noted in AD brain since Alzheimer’s initial observations, recent studies have shown abnormal white matter in every AD brain. Moreover, there is age-related WM injury in normal individuals that occurs earlier and is worse with the APOE4 genotype. Moreover, WM injury precedes formation of plaques and tangles in human Familial Alzheimer’s disease (FAD) and precedes plaque formation in rodent AD models. Restoring WM in rodent AD models improves cognition without affecting AD pathology. Thus, we postulate that the amyloid cascade, cholesterol dysmetabolism and white matter injury interact to produce and/or worsen AD pathology. We further postulate that the primary initiating event could be related to any of the three, with age a major factor for WM injury, diet and APOE4 and other genes a factor for cholesterol dysmetabolism, and FAD and other genes for Abeta dysmetabolism.

Background Intracerebral hemorrhage (ICH) has a high morbidity and mortality. The peripheral immune system and cross-talk between peripheral blood and brain have been implicated in the ICH immune response. Thus, we delineated the gene networks associated with human ICH in the peripheral blood transcriptome. We also compared the differentially expressed genes in blood following ICH to a prior human study of perihematomal brain tissue. Methods We performed peripheral blood whole-transcriptome analysis of ICH and matched vascular risk factor control subjects ( n  = 66). Gene co-expression network analysis identified groups of co-expressed genes (modules) associated with ICH and their most interconnected genes (hubs). Mixed-effects regression identified differentially expressed genes in ICH compared to controls. Results Of seven ICH-associated modules, six were enriched with cell-specific genes: one neutrophil module, one neutrophil plus monocyte module, one T cell module, one Natural Killer cell module, and two erythroblast modules. The neutrophil/monocyte modules were enriched in inflammatory/immune pathways; the T cell module in T cell receptor signaling genes; and the Natural Killer cell module in genes regulating alternative splicing, epigenetic, and post-translational modifications. One erythroblast module was enriched in autophagy pathways implicated in experimental ICH, and NRF2 signaling implicated in hematoma clearance. Many hub genes or module members, such as IARS, mTOR, S1PR1, LCK, FYN, SKAP1, ITK, AMBRA1, NLRC4, IL6R, IL17RA, GAB2, MXD1, PIK3CD, NUMB, MAPK14, DDX24, EVL, TDP1, ATG3, WDFY3, GSK3B, STAT3, STX3, CSF3R, PIP4K2A, ANXA3, DGAT2, LRP10, FLOT2, ANK1, CR1, SLC4A1, and DYSF, have been implicated in neuroinflammation, cell death, transcriptional regulation, and some as experimental ICH therapeutic targets. Gene-level analysis revealed 1225 genes (FDR p  < 0.05, fold-change > |1.2|) have altered expression in ICH in peripheral blood. There was significant overlap of the 1225 genes with dysregulated genes in human perihematomal brain tissue ( p  = 7 × 10 −3 ). Overlapping genes were enriched for neutrophil-specific genes ( p  = 6.4 × 10 −08 ) involved in interleukin, neuroinflammation, apoptosis, and PPAR signaling. Conclusions This study delineates key processes underlying ICH pathophysiology, complements experimental ICH findings, and the hub genes significantly expand the list of novel ICH therapeutic targets. The overlap between blood and brain gene responses underscores the importance of examining blood-brain interactions in human ICH.