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Cerebral blood flow (CBF) reductions in Alzheimer's disease patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences for Alzheimer's disease pathogenesis remain poorly understood. In APP/PS1 and 5xFAD mice we found that an increased number of cortical capillaries had stalled blood flow as compared to in wild-type animals, largely due to neutrophils that had adhered in capillary segments and blocked blood flow. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to both an immediate increase in CBF and rapidly improved performance in spatial and working memory tasks. This study identified a previously uncharacterized cellular mechanism that explains the majority of the CBF reduction seen in two mouse models of Alzheimer's disease and demonstrated that improving CBF rapidly enhanced short-term memory function. Restoring cerebral perfusion by preventing neutrophil adhesion may provide a strategy for improving cognition in Alzheimer's disease patients.

Purpose. The Gram-positive Staphylococcus aureus bacterium is one of the leading causes of infection in humans. The lack of specific noninvasive techniques for diagnosis of staphylococcal infection together with the severity of its associated complications support the need for new specific and selective diagnostic tools. This work presents the successful synthesis of an immunotracer that targets the α-toxin released by S. aureus. Methods. [89Zr]Zr-DFO-ToxAb was synthesized based on radiolabeling an anti-α-toxin antibody with zirconium-89. The physicochemical characterization of the immunotracer was performed by high-performance liquid chromatography (HPLC), radio-thin layer chromatography (radio-TLC), and electrophoretic analysis. Its diagnostic ability was evaluated in vivo by positron emission tomography/computed tomography (PET/CT) imaging in an animal model of local infection-inflammation (active S. aureus vs. heat-killed S. aureus) and infective osteoarthritis. Results. Chemical characterization of the tracer established the high radiochemical yield and purity of the tracer while maintaining antibody integrity. In vivo PET/CT image confirmed the ability of the tracer to detect active foci of S. aureus. Those results were supported by ex vivo biodistribution studies, autoradiography, and histology, which confirmed the ability of [89Zr]Zr-DFO-ToxAb to detect staphylococcal infectious foci, avoiding false-positives derived from inflammatory processes. Conclusions. We have developed an immuno-PET tracer capable of detecting S. aureus infections based on a radiolabeled antibody specific for the staphylococcal alpha toxins. The in vivo assessment of [89Zr]Zr-DFO-ToxAb confirmed its ability to selectively detect staphylococcal infectious foci, allowing us to discern between infectious and inflammatory processes. [ABSTRACT FROM AUTHOR]

LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and cardiovascular disease (CVD) are strongly associated. Both are multifactorial disorders with long asymptomatic phases and similar risk factors. Indeed, CVD signatures such as cerebral microbleeds, micro‐infarcts, atherosclerosis, cerebral amyloid angiopathy and a procoagulant state are highly associated with AD. However, AD and CVD co‐development and the molecular mechanisms underlying such associations are not understood. Here, we review the evidence regarding the vascular component of AD and clinical studies using anticoagulants that specifically evaluated the development of AD and other dementias. Most studies reported a markedly decreased incidence of composite dementia in anticoagulated patients with atrial fibrillation, with the highest benefit for direct oral anticoagulants. However, sub‐analyses by differential dementia diagnosis were scarce and inconclusive. We finally discuss whether anticoagulation could be a plausible preventive/therapeutic approach for AD and, if so, which would be the best drug and strategy to maximize clinical benefit and minimize potential risks. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc [ABSTRACT FROM AUTHOR]

Growing evidence supports the suggestion that the peripheral immune system plays a role in different pathologies associated with cognitive impairment, such as vascular dementia (VD) or Alzheimer's disease (AD). The aim of this review is to summarize, within the peripheral immune system, the implications of different types of myeloid cells in AD and VD, with a special focus on post‐stroke cognitive impairment and dementia (PSCID). We will review the contributions of the myeloid lineage, from peripheral cells (neutrophils, platelets, monocytes and monocyte‐derived macrophages) to central nervous system (CNS)‐associated cells (perivascular macrophages and microglia). Finally, we will evaluate different potential strategies for pharmacological modulation of pathological processes mediated by myeloid cell subsets, with an emphasis on neutrophils, their interaction with platelets and the process of immunothrombosis that triggers neutrophil‐dependent capillary stall and hypoperfusion, as possible effector mechanisms that may pave the way to novel therapeutic avenues to stop dementia, the epidemic of our time. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc [ABSTRACT FROM AUTHOR]

Increasing evidence supports a vascular contribution to Alzheimer's disease (AD), but a direct connection between AD and the circulatory system has not been established. Previous work has shown that blood clots formed in the presence of the [beta]-amyloid peptide (A[beta]), which has been implicated in AD, have an abnormal structure and are resistant to degradation in vitro and in vivo. In the present study, we show that A[beta] specifically interacts with fibrinogen with a [K.sub.d] of 26.3 [+ or -] 6.7 nM, that the binding site is located near the C terminus of the fibrinogen [beta]-chain, and that the binding causes fibrinogen to oligomerize. These results suggest that the interaction between A[beta] and fibrinogen modifies fibrinogen's structure, which may then lead to abnormal fibrin clot formation. Overall, our study indicates that the interaction between A[beta] and fibrinogen may be an important contributor to the vascular abnormalities found in AD. doi: 10.1073/pnas.1010373107

Background: Atherosclerosis has been linked to cognitive decline in late life; however, the impact of cardiovascular risk factors (CVRFs) and subclinical atherosclerosis on brain metabolism at earlier stages remains unexplored. Method: This study, aimed at determining the association between brain metabolism, subclinical atherosclerosis and CVRFs in midlife, included 547 asymptomatic middle‐aged participants (50±4 years, 82% men) from the Progression of Early Subclinical Atherosclerosis study with evidence of subclinical atherosclerosis. Participants underwent 18F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET). Global brain FDG uptake and voxel‐wise analyses were used to evaluate the associations of cerebral metabolism with CVRFs and atherosclerotic plaque burden in carotids and femorals assessed by 3D‐vascular ultrasound. Result: Global FDG uptake showed an inverse correlation with 30‐year Framingham Risk Score (30y‐FRS) (β=‐0.15, p<0.001). This association was mainly driven by the presence of hypertension (d=0.36, p<0.001). Carotid plaque burden was inversely associated with global brain FDG uptake (β=‐0.16, p<0.001), even after adjusting for 30y‐FRS. Voxel‐wise approaches revealed that the brain areas most strongly affected by hypometabolism in association with 30y‐FRS, hypertension, and carotid plaque burden were parietotemporal regions (angular, supramarginal, and inferior/middle temporal gyri) and the cingulate gyrus. Conclusion: In asymptomatic middle‐aged individuals, cardiovascular risk is associated with brain hypometabolism, with hypertension being the modifiable CVRF showing the strongest association. Subclinical carotid plaque burden is also linked to reduced brain metabolism independently of CVRFs. Cerebral areas showing hypometabolism include mainly those known to be affected in Alzheimer´s disease. These results suggest that the interplay between cardiovascular disease and altered brain metabolism starts early in life, many years before the clinical manifestation. Understanding the extent to which cardiovascular risk factors influence brain´s vulnerability early in the course of atherosclerosis may help to refine preventive strategies and reduce the incidence of dementia in late life. [ABSTRACT FROM AUTHOR]

Background The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor, which was first identified as a regulator of differentiation and inflammatory processes mainly in adipose tissue and liver; however, its function in the brain was largely unknown for many years. Previous studies from our laboratory indicated that C/EBPβ is implicated in inflammatory process and brain injury, since mice lacking this gene were less susceptible to kainic acid-induced injury. Methods We first performed cDNA microarrays analysis using hippocampal RNA isolated from C/EBPβ+/+ and C/EBPβ-/- mice. Immunocytochemical and immunohistochemical studies were done to evaluate C/EBPβ and C3 levels. Transient transfection experiments were made to analyze transcriptional regulation of C3 by C/EBPβ. To knockdown C/EBPβ and C3 expression, mouse astrocytes were infected with lentiviral particles expressing an shRNA specific for C/EBPβ or an siRNA specific for C3. Results Among the genes displaying significant changes in expression was complement component 3 (C3), which showed a dramatic decrease in mRNA content in the hippocampus of C/EBPβ-/- mice. C3 is the central component of the complement and is implicated in different brain disorders. In this work we have found that C/EBPβ regulates C3 levels in rodents glial in vitro and in the rat Substantia nigra pars compacta (SNpc) in vivo following an inflammatory insult. Analysis of the mouse C3 promoter showed that it is directly regulated by C/EBPβ through a C/EBPβ consensus site located at position -616/-599 of the gene. In addition, we show that depletion of C/EBPβ by a specific shRNA results in a significant decrease in the levels of C3 together with a reduction in the increased levels of pro-inflammatory agents elicited by lipopolysaccharide treatment. Conclusions Altogether, these results indicate that C3 is a downstream target of C/EBPβ, and it could be a mediator of the pro-inflammatory effects of this transcription factor in neural cells. [ABSTRACT FROM AUTHOR]

Increasing evidence supports a vascular contribution to Alzheimer's disease (AD). but a direct connection between AD and the circulatory system has not been established. Previous work has shown that blood clots formed in the presence of the β-amyloid peptide (Aβ), which has been implicated in AD, have an abnormal structure and are resistant to degradation in vitro and in vivo. In the present study, we show that Aβ specifically interacts with fibrinogen with a Kd of 26.3 ± 6.7 nM, that the binding site is located near the C terminus of the fibrinogen β-chain, and that the binding causes fibrinogen to oligomerize. These results suggest that the interaction between Aβ and fibrinogen modifies fibrinogen's structure, which may then lead to abnormal fibrin clot formation. Overall, our study indicates that the interaction between Aβ and fibrinogen may be an important contributor to the vascular abnormalities found in AD. [ABSTRACT FROM AUTHOR]

Inflammation and neurodegeneration coexist in many acute damage and chronic CNS disorders (e.g., stroke, Alzheimer's disease, Parkinson's disease). A well characterized animal model of brain damage involves administration of kainic acid, which causes limbic seizure activity and subsequent neuronal death, especially in the CA1 and CA3 pyramidal cells and interneurons in the hilus of the hippocampus. Our previous work demonstrated a potent anti-inflammatory and neuroprotective effect of two thiadiazolidinones compounds, NP00111 (2,4-dibenzyl-[1,2,4]thiadiazolidine-3,5-dione) and NP01138 (2-ethyl-4-phenyl-[1,2,4]thiadiazolidine-3,5-dione), in primary cultures of cortical neurons, astrocytes, and microglia. Here, we show that injection of NP031112, a more potent thiadiazolidinone derivative, into the rat hippocampus dramatically reduces kainic acid-induced inflammation, as measured by edema formation using T2-weighted magnetic resonance imaging and glial activation and has a neuroprotective effect in the damaged areas of the hippocampus. Last, NP031112-induced neuroprotection, both in vitro and in vivo, was substantially attenuated by cotreatment with GW9662 (2-chloro-5-nitrobenzanilide), a known antagonist of the nuclear receptor peroxisome proliferator-activated receptor γ, suggesting that the effects of NP031112 can be mediated through activation of this receptor. As such, these findings identify NP031112 as a potential therapeutic agent for the treatment of neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the beta-amyloid peptide (Abeta) is a critical factor in this disease, we examined its relationship to fibrin clot formation in AD. In vitro and in vivo experiments showed that fibrin clots formed in the presence of Abeta are structurally abnormal and resistant to degradation. Fibrin(ogen) was observed in blood vessels positive for amyloid in mouse and human AD samples, and intravital brain imaging of clot formation and dissolution revealed abnormal thrombosis and fibrinolysis in AD mice. Moreover, depletion of fibrinogen lessened cerebral amyloid angiopathy pathology and reduced cognitive impairment in AD mice. These experiments suggest that one important contribution of Abeta to AD is via its effects on fibrin clots, implicating fibrin(ogen) as a potential critical factor in this disease., (Copyright 2010 Elsevier Inc. All rights reserved.)

The CCAAT/enhancer-binding protein beta (C/EBPbeta, also known as CEBPB) was first identified as a regulator of differentiation and inflammatory processes in adipose tissue and liver. Although C/EBPbeta was initially implicated in synaptic plasticity, its function in the brain remains largely unknown. We have previously shown that C/EBPbeta regulates the expression of genes involved in inflammatory processes and brain injury. Here, we have demonstrated that the expression of C/EBPbeta is notably increased in the hippocampus in a murine model of excitotoxicity. Mice lacking C/EBPbeta showed a reduced inflammatory response after kainic acid injection, and exhibited a dramatic reduction in pyramidal cell loss in the CA1 and CA3 subfields of the hippocampus. These data reveal an essential function for C/EBPbeta in the pathways leading to excitotoxicity-mediated damage and suggest that inhibitors of this transcription factor should be evaluated as possible neuroprotective therapeutic agents.

In most neurodegenerative disorders, including multiple sclerosis, Parkinson disease, and Alzheimer disease, a massive neuronal cell death occurs as a consequence of an uncontrolled inflammatory response, where activated astrocytes and microglia and their cytotoxic agents play a crucial pathological role. Current treatments for these diseases are not effective. In the present study we investigate the effect of thiadiazolidinone derivatives, which have been recently suggested to play a role in neurodegenerative disorders. We have found that thiadiazolidinones are potent neuroprotector compounds. Thiadiazolidinones inhibited inflammatory activation of cultured brain astrocytes and microglia by diminishing lipopolysaccharide-induced interleukin 6, tumor necrosis factor alpha, inducible nitric-oxide synthase, and inducible cyclooxygenase type 2 expression. In addition, thiadiazolidinones inhibited tumor necrosis factor-alpha and nitric oxide production and, concomitantly, protected cortical neurons from cell death induced by the cell-free supernatant from activated microglia. The neuroprotective effects of thiadiazolidinones are completely inhibited by the peroxisome proliferator-activated receptor gamma antagonist GW9662. In contrast the glycogen synthase kinase 3beta inhibitor LiCl did not show any effect. These findings suggest that thiadiazolidinones potently attenuate lipopolysaccharide-induced neuroinflammation and reduces neuronal death by a mechanism dependent of peroxisome proliferator-activated receptor gamma activation.