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1.
Exp Neurol ; 324: 113116, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31734317

RESUMO

Traumatic brain injury (TBI) is a leading cause of death and disability in modern societies. Diffuse axonal and vascular injury are nearly universal consequences of mechanical energy impacting the head and contribute to disability throughout the injury severity spectrum. CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) is a non-surgical, impact-acceleration model of rodent TBI that reliably produces diffuse axonal injury characterized by white matter gliosis and axonal damage. At impact energies up to 0.7 joules, which result in mild TBI in mice, CHIMERA does not produce detectable vascular or grey matter injury. This study was designed to expand CHIMERA's capacity to induce more severe injuries, including vascular damage and grey matter gliosis. This was made possible by designing a physical interface positioned between the piston and animal's head to allow higher impact energies to be transmitted to the head without causing skull fracture. Here, we assessed interface-assisted single CHIMERA TBI at 2.5 joules in wild-type mice using a study design that spanned 6 h-60 d time points. Injured animals displayed robust acute neurological deficits, elevated plasma total tau and neurofilament-light levels, transiently increased proinflammatory cytokines in brain tissue, blood-brain barrier (BBB) leakage and microstructural vascular abnormalities, and grey matter microgliosis. Memory deficits were evident at 30 d and resolved by 60 d. Intriguingly, white matter injury was not remarkable at acute time points but evolved over time, with white matter gliosis being most extensive at 60 d. Interface-assisted CHIMERA thus enables experimental modeling of distinct endophenotypes of TBI that include acute vascular and grey matter injury in addition to chronic evolution of white matter damage, similar to the natural history of human TBI.

2.
Neuron ; 103(3): 367-379, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31394062

RESUMO

Traumatic brain injury (TBI) is one the most common human afflictions, contributing to long-term disability in survivors. Emerging data indicate that functional improvement or deterioration can occur years after TBI. In this regard, TBI is recognized as risk factor for late-life neurodegenerative disorders. TBI encompasses a heterogeneous disease process in which diverse injury subtypes and multiple molecular mechanisms overlap. To develop precision medicine approaches where specific pathobiological processes are targeted by mechanistically appropriate therapies, techniques to identify and measure these subtypes are needed. Traumatic microvascular injury is a common but relatively understudied TBI endophenotype. In this review, we describe evidence of microvascular dysfunction in human and animal TBI, explore the role of vascular dysfunction in neurodegenerative disease, and discuss potential opportunities for vascular-directed therapies in ameliorating TBI-related neurodegeneration. We discuss the therapeutic potential of vascular-directed therapies in TBI and the use and limitations of preclinical models to explore these therapies.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Circulação Cerebrovascular , Microvasos/patologia , Doenças Neurodegenerativas/etiologia , Acoplamento Neurovascular , Animais , Barreira Hematoencefálica , Lesões Encefálicas Traumáticas/fisiopatologia , Isquemia Encefálica/etiologia , Progressão da Doença , Endotélio Vascular/fisiopatologia , Humanos , Microcirculação , Micronutrientes/farmacocinética , Modelos Animais , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/prevenção & controle , Neuroimagem
3.
Sci Rep ; 9(1): 9870, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285517

RESUMO

Advances in the understanding of Alzheimer's disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic amyloid-beta oligomers (AßO). Therapeutic antibodies targeting Aß monomers and/or plaque have shown limited efficacy and dose-limiting adverse events in clinical trials. These findings suggest that antibodies capable of selectively neutralizing toxic AßO may achieve improved efficacy and safety. To this end, we generated monoclonal antibodies against a conformational Aß epitope predicted by computational modeling to be presented on toxic AßO but not monomers or fibrils. The resulting lead antibody, PMN310, showed the desired AßO-selective binding profile. In vitro, PMN310 inhibited AßO propagation and toxicity. In vivo, PMN310 prevented AßO-induced loss of memory formation and reduced synaptic loss and inflammation. A humanized version (huPMN310) compared favorably to other Aß-directed antibodies showing a lack of adverse event-associated binding to Aß deposits in AD brains, and greater selective binding to AßO-enriched AD brain fractions that contain synaptotoxic Aß species. Systemic administration of huPMN310 in mice resulted in brain exposure and kinetics comparable to those of other therapeutic human monoclonal antibodies. Greater selectivity for AßO and the potential to safely administer high doses of huPMN310 are expected to result in enhanced safety and therapeutic potency.

4.
Alzheimers Res Ther ; 11(1): 44, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31084613

RESUMO

BACKGROUND: Alzheimer's disease (AD) is defined by amyloid beta (Aß) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aß deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aß deposition and Aß-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aß pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice. METHODS: APP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aß protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior. RESULTS: In APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aß deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRß protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aß or associated with Aß plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed. CONCLUSIONS: ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.

5.
Curr Opin Lipidol ; 30(3): 224-234, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30946049

RESUMO

PURPOSE OF REVIEW: We review current knowledge regarding HDL and Alzheimer's disease, focusing on HDL's vasoprotective functions and potential as a biomarker and therapeutic target for the vascular contributions of Alzheimer's disease. RECENT FINDINGS: Many epidemiological studies have observed that circulating HDL levels associate with decreased Alzheimer's disease risk. However, it is now understood that the functions of HDL may be more informative than levels of HDL cholesterol (HDL-C). Animal model studies demonstrate that HDL protects against memory deficits, neuroinflammation, and cerebral amyloid angiopathy (CAA). In-vitro studies using state-of-the-art 3D models of the human blood-brain barrier (BBB) confirm that HDL reduces vascular Aß accumulation and attenuates Aß-induced endothelial inflammation. Although HDL-based therapeutics have not been tested in clinical trials for Alzheimer's disease , several HDL formulations are in advanced phase clinical trials for coronary artery disease and atherosclerosis and could be leveraged toward Alzheimer's disease . SUMMARY: Evidence from human studies, animal models, and bioengineered arteries supports the hypothesis that HDL protects against cerebrovascular dysfunction in Alzheimer's disease. Assays of HDL functions relevant to Alzheimer's disease may be desirable biomarkers of cerebrovascular health. HDL-based therapeutics may also be of interest for Alzheimer's disease, using stand-alone or combination therapy approaches.

6.
Exp Neurol ; 317: 87-99, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30822421

RESUMO

Traumatic brain injury (TBI) affects at least 3 M people annually. In humans, repetitive mild TBI (rmTBI) can lead to increased impulsivity and may be associated with chronic traumatic encephalopathy. To better understand the relationship between repetitive TBI (rTBI), impulsivity and neuropathology, we used CHIMERA (Closed-Head Injury Model of Engineered Rotational Acceleration) to deliver five TBIs to rats, which were continuously assessed for trait impulsivity using the delay discounting task and for neuropathology at endpoint. Compared to sham controls, rats with rTBI displayed progressive impairment in impulsive choice. Histological analyses revealed reduced dopaminergic innervation from the ventral tegmental area to the olfactory tubercle, consistent with altered impulsivity neurocircuitry. Consistent with diffuse axonal injury generated by CHIMERA, white matter inflammation, tau immunoreactivity and degeneration were observed in the optic tract and corpus callosum. Finally, pronounced grey matter microgliosis was observed in the olfactory tubercle. Our results provide insight into the mechanisms by which rTBI leads to post-traumatic psychiatric-like symptoms in a novel rat TBI platform.

7.
Int J Mol Sci ; 20(3)2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30678190

RESUMO

High-density lipoproteins (HDL) are known to have vasoprotective functions in peripheral arteries and many of these functions extend to brain-derived endothelial cells. Importantly, several novel brain-relevant HDL functions have been discovered using brain endothelial cells and in 3D bioengineered human arteries. The cerebrovascular benefits of HDL in healthy humans may partly explain epidemiological evidence suggesting a protective association of circulating HDL levels against Alzheimer's Disease (AD) risk. As several methods exist to prepare HDL from plasma, here we compared cerebrovascular functions relevant to AD using HDL isolated by density gradient ultracentrifugation relative to apoB-depleted plasma prepared by polyethylene-glycol precipitation, a common high-throughput method to evaluate HDL cholesterol efflux capacity in clinical biospecimens. We found that apoB-depleted plasma was functionally equivalent to HDL isolated by ultracentrifugation in terms of its ability to reduce vascular Aß accumulation, suppress TNFα-induced vascular inflammation and delay Aß fibrillization. However, only HDL isolated by ultracentrifugation was able to suppress Aß-induced vascular inflammation, improve Aß clearance, and induce endothelial nitric oxide production.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Apolipoproteínas B/deficiência , Lipoproteínas HDL/sangue , Lipoproteínas HDL/metabolismo , Plasma/metabolismo , Adulto , Peptídeos beta-Amiloides/metabolismo , Bioengenharia , Barreira Hematoencefálica/metabolismo , Células Cultivadas , Angiopatia Amiloide Cerebral/sangue , Angiopatia Amiloide Cerebral/metabolismo , Células Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Inflamação/sangue , Inflamação/metabolismo , Masculino , Monócitos/citologia , Monócitos/metabolismo , Óxido Nítrico/metabolismo , Adulto Jovem
8.
Alzheimers Dement ; 15(1): 158-167, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30642436

RESUMO

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.


Assuntos
Doença de Alzheimer/fisiopatologia , Biomarcadores , Doenças Vasculares/fisiopatologia , Substância Branca/patologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/patologia , Circulação Cerebrovascular/fisiologia , Humanos , National Institute on Aging (U.S.) , Estados Unidos
9.
Alzheimers Res Ther ; 11(1): 6, 2019 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-30636629

RESUMO

BACKGROUND: The annual incidence of traumatic brain injury (TBI) in the United States is over 2.5 million, with approximately 3-5 million people living with chronic sequelae. Compared with moderate-severe TBI, the long-term effects of mild TBI (mTBI) are less understood but important to address, particularly for contact sport athletes and military personnel who have high mTBI exposure. The purpose of this study was to determine the behavioural and neuropathological phenotypes induced by the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of mTBI in both wild-type (WT) and APP/PS1 mice up to 8 months post-injury. METHODS: Male WT and APP/PS1 littermates were randomized to sham or repetitive mild TBI (rmTBI; 2 × 0.5 J impacts 24 h apart) groups at 5.7 months of age. Animals were assessed up to 8 months post-injury for acute neurological deficits using the loss of righting reflex (LRR) and Neurological Severity Score (NSS) tasks, and chronic behavioural changes using the passive avoidance (PA), Barnes maze (BM), elevated plus maze (EPM) and rotarod (RR) tasks. Neuropathological assessments included white matter damage; grey matter inflammation; and measures of Aß levels, deposition, and aducanumab binding activity. RESULTS: The very mild CHIMERA rmTBI conditions used here produced no significant acute neurological or motor deficits in WT and APP/PS1 mice, but they profoundly inhibited extinction of fear memory specifically in APP/PS1 mice over the 8-month assessment period. Spatial learning and memory were affected by both injury and genotype. Anxiety and risk-taking behaviour were affected by injury but not genotype. CHIMERA rmTBI induced chronic white matter microgliosis, axonal injury and astrogliosis independent of genotype in the optic tract but not the corpus callosum, and it altered microgliosis in APP/PS1 amygdala and hippocampus. Finally, rmTBI did not alter long-term tau, Aß or amyloid levels, but it increased aducanumab binding activity. CONCLUSIONS: CHIMERA is a useful model to investigate the chronic consequences of rmTBI, including behavioural abnormalities consistent with features of post-traumatic stress disorder and inflammation of both white and grey matter. The presence of human Aß greatly modified extinction of fear memory after rmTBI.

10.
Neuroinformatics ; 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30406865

RESUMO

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Detailed studies of the microglial response after TBI require high throughput quantification of changes in microglial count and morphology in histological sections throughout the brain. In this paper, we present a fully automated end-to-end system that is capable of assessing microglial activation in white matter regions on whole slide images of Iba1 stained sections. Our approach involves the division of the full brain slides into smaller image patches that are subsequently automatically classified into white and grey matter sections. On the patches classified as white matter, we jointly apply functional minimization methods and deep learning classification to identify Iba1-immunopositive microglia. Detected cells are then automatically traced to preserve their complex branching structure after which fractal analysis is applied to determine the activation states of the cells. The resulting system detects white matter regions with 84% accuracy, detects microglia with a performance level of 0.70 (F1 score, the harmonic mean of precision and sensitivity) and performs binary microglia morphology classification with a 70% accuracy. This automated pipeline performs these analyses at a 20-fold increase in speed when compared to a human pathologist. Moreover, we have demonstrated robustness to variations in stain intensity common for Iba1 immunostaining. A preliminary analysis was conducted that indicated that this pipeline can identify differences in microglia response due to TBI. An automated solution to microglia cell analysis can greatly increase standardized analysis of brain slides, allowing pathologists and neuroscientists to focus on characterizing the associated underlying diseases and injuries.

11.
ACS Chem Neurosci ; 9(7): 1591-1606, 2018 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-29614860

RESUMO

Oligomers of amyloid-ß (AßO) are deemed key in synaptotoxicity and amyloid seeding of Alzheimer's disease (AD). However, the heterogeneous and dynamic nature of AßO and inadequate markers for AßO subtypes have stymied effective AßO identification and therapeutic targeting in vivo. We identified an AßO-subclass epitope defined by differential solvent orientation of the lysine 28 side chain in a constrained loop of serine-asparagine-lysine (cSNK), rarely displayed in molecular dynamics simulations of monomer and fibril ensembles. A mouse monoclonal antibody targeting AßOcSNK recognizes ∼50-60 kDa SDS-resistant soluble Aß assemblages in AD brain and prolongs the lag phase of Aß aggregation in vitro. Acute peripheral infusion of a murine IgG1 anti-AßOcSNK in two AD mouse models reduced soluble brain Aß aggregates by 20-30%. Chronic cSNK peptide immunization of APP/PS1 mice engendered an anti-AßOcSNK IgG1 response without epitope spreading to Aß monomers or fibrils and was accompanied by preservation of global PSD95 expression and improved cued fear memory. Our data indicate that the oligomer subtype AßOcSNK participates in synaptotoxicity and propagation of Aß aggregation in vitro and in vivo.

12.
J Lipid Res ; 59(5): 830-842, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29563219

RESUMO

apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer's disease (AD). apoE is primarily lipidated via ABCA1, and both are under transcriptional regulation by the nuclear liver X receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden. However, direct synthetic LXR ligands have hepatotoxic side effects that limit their clinical use. Here, we describe a set of small molecules, previously annotated as antagonists of the purinergic receptor, P2X7, which enhance ABCA1 expression and activity as well as apoE secretion, and are not direct LXR ligands. Furthermore, P2X7 is not required for these molecules to induce ABCA1 upregulation and apoE secretion, demonstrating that the ABCA1 and apoE effects are mechanistically independent of P2X7 inhibition. Hence, we have identified novel dual activity compounds that upregulate ABCA1 across multiple CNS cell types, including human astrocytes, pericytes, and microglia, through an indirect LXR mechanism and that also independently inhibit P2X7 receptor activity.

13.
Exp Neurol ; 301(Pt A): 26-38, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29269117

RESUMO

Peak incidence of traumatic brain injury (TBI) occurs in both young and old individuals, and older age at injury is associated with worse outcome and poorer recovery. Moderate-severe TBI is a reported risk factor for dementia, including Alzheimer's disease (AD), but whether mild TBI (mTBI) alters AD pathogenesis is not clear. To delineate how age at injury and predisposition to amyloid formation affect the acute response to mTBI, we used the Closed Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of TBI to induce two mild injuries in wild-type (WT) and APP/PS1 mice at either 6 or 13months of age and assessed behavioural, histological and biochemical changes up to 14days post-injury. Age at injury did not alter acute behavioural responses to mTBI, including measures of neurological status, motor performance, spatial memory, fear, or anxiety, in either strain. Young APP/PS1 mice showed a subtle and transient increase in diffuse Aß deposits after injury, whereas old APP/PS1 mice showed decreased amyloid deposits, without significant alterations in total soluble or insoluble Aß levels at either age. Age at injury and genotype showed complex responses with respect to microglial and cytokine outcomes, where post-injury neuroinflammation is increased in old WT mice but attenuated in old APP/PS1 mice. Intriguingly, silver staining confirmed axonal damage in both strains and ages, yet only young WT and APP/PS1 mice showed neurofilament-positive axonal swellings after mTBI, as this response was almost entirely attenuated in old mice. Plasma neurofilament-light levels were significantly elevated after injury only in young APP/PS1 mice. This study suggests that mild TBI has minimal effects on Aß metabolism, but that age and genotype can each modify acute outcomes related to white matter injury.


Assuntos
Doença de Alzheimer , Concussão Encefálica/patologia , Encéfalo/patologia , Substância Branca/patologia , Fatores Etários , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Genótipo , Inflamação/patologia , Filamentos Intermediários/metabolismo , Camundongos , Camundongos Transgênicos
14.
Elife ; 62017 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-28994390

RESUMO

Amyloid plaques, consisting of deposited beta-amyloid (Aß), are a neuropathological hallmark of Alzheimer's Disease (AD). Cerebral vessels play a major role in AD, as Aß is cleared from the brain by pathways involving the cerebrovasculature, most AD patients have cerebrovascular amyloid (cerebral amyloid angiopathy (CAA), and cardiovascular risk factors increase dementia risk. Here we present a notable advance in vascular tissue engineering by generating the first functional 3-dimensioinal model of CAA in bioengineered human vessels. We show that lipoproteins including brain (apoE) and circulating (high-density lipoprotein, HDL) synergize to facilitate Aß transport across bioengineered human cerebral vessels. These lipoproteins facilitate Aß42 transport more efficiently than Aß40, consistent with Aß40 being the primary species that accumulates in CAA. Moreover, apoE4 is less effective than apoE2 in promoting Aß transport, also consistent with the well-established role of apoE4 in Aß deposition in AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Vasos Sanguíneos/metabolismo , Angiopatia Amiloide Cerebral/fisiopatologia , Lipoproteínas HDL/metabolismo , Bioengenharia , Humanos , Modelos Biológicos , Técnicas de Cultura de Órgãos , Transporte Proteico
15.
Mol Neurodegener ; 12(1): 60, 2017 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-28830501

RESUMO

BACKGROUND: Alzheimer's Disease (AD), characterized by accumulation of beta-amyloid (Aß) plaques in the brain, can be caused by age-related failures to clear Aß from the brain through pathways that involve the cerebrovasculature. Vascular risk factors are known to increase AD risk, but less is known about potential protective factors. We hypothesize that high-density lipoproteins (HDL) may protect against AD, as HDL have vasoprotective properties that are well described for peripheral vessels. Epidemiological studies suggest that HDL is associated with reduced AD risk, and animal model studies support a beneficial role for HDL in selectively reducing cerebrovascular amyloid deposition and neuroinflammation. However, the mechanism by which HDL may protect the cerebrovascular endothelium in the context of AD is not understood. METHODS: We used peripheral blood mononuclear cell adhesion assays in both a highly novel three dimensional (3D) biomimetic model of the human vasculature composed of primary human endothelial cells (EC) and smooth muscle cells cultured under flow conditions, as well as in monolayer cultures of ECs, to study how HDL protects ECs from the detrimental effects of Aß. RESULTS: Following Aß addition to the abluminal (brain) side of the vessel, we demonstrate that HDL circulated within the lumen attenuates monocyte adhesion to ECs in this biofidelic vascular model. The mechanism by which HDL suppresses Aß-mediated monocyte adhesion to ECs was investigated using monotypic EC cultures. We show that HDL reduces Aß-induced PBMC adhesion to ECs independent of nitric oxide (NO) production, miR-233 and changes in adhesion molecule expression. Rather, HDL acts through scavenger receptor (SR)-BI to block Aß uptake into ECs and, in cell-free assays, can maintain Aß in a soluble state. We confirm the role of SR-BI in our bioengineered human vessel. CONCLUSION: Our results define a novel activity of HDL that suppresses Aß-mediated monocyte adhesion to the cerebrovascular endothelium.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Leucócitos Mononucleares/metabolismo , Lipoproteínas HDL/metabolismo , Doença de Alzheimer/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Monócitos/metabolismo , Placa Amiloide/metabolismo
16.
J Neurotrauma ; 34(19): 2790-2800, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28376700

RESUMO

Traumatic brain injury (TBI) is associated with the development of numerous psychiatric diseases. Of particular concern for TBI patients is the impact of chronic impulsivity on daily functioning. Despite the scope of the human problem, little has been done to address impulsivity in animal models of brain injury. In the current study, we examined the effects of either a severe or a milder bilateral frontal controlled cortical impact injury on impulsivity using the Delay Discounting Task (DDT), in which preference for smaller-sooner over larger-later rewards is indicative of greater impulsive choice. Both milder and severe TBI caused a significant, chronic increase in impulsive decision making. Despite these pronounced changes in performance of the DDT, memory function, as assessed by the Morris Water Maze, was not impaired in more mildly injured rats and only transiently impacted in the severe TBI group. Whereas a significant lesion was only evident in severely injured rats, analysis of cytokine levels within the frontal cortex revealed a selective increase in interleukin (IL)-12 that was associated with the magnitude of the change in impulsive choice caused by both milder and severe TBI. These findings suggest that tissue loss alone cannot explain the increased impulsivity observed, and that inflammatory pathways mediated by IL-12 may be a contributing factor. The findings from this study highlight the sensitivity of sophisticated behavioral measures designed to assess neuropsychiatric dysfunction in the detection of TBI-induced cognitive impairments and their utility in identifying potential mechanistic pathways and therapeutic targets.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/patologia , Tomada de Decisões , Comportamento Impulsivo , Interleucina-12/metabolismo , Animais , Comportamento Animal/fisiologia , Lesões Encefálicas Traumáticas/psicologia , Lobo Frontal/lesões , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Masculino , Ratos , Ratos Long-Evans
17.
Exp Neurol ; 292: 80-91, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28274861

RESUMO

CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) is a recently described animal model of traumatic brain injury (TBI) that primarily produces diffuse axonal injury (DAI) characterized by white matter inflammation and axonal damage. CHIMERA was specifically designed to reliably generate a variety of TBI severities using precise and quantifiable biomechanical inputs in a nonsurgical user-friendly platform. The objective of this study was to define the lower limit of single impact mild TBI (mTBI) using CHIMERA by characterizing the dose-response relationship between biomechanical input and neurological, behavioral, neuropathological and biochemical outcomes. Wild-type male mice were subjected to a single CHIMERA TBI using six impact energies ranging from 0.1 to 0.7J, and post-TBI outcomes were assessed over an acute period of 14days. Here we report that single TBI using CHIMERA induces injury dose- and time-dependent changes in behavioral and neurological deficits, axonal damage, white matter tract microgliosis and astrogliosis. Impact energies of 0.4J or below produced no significant phenotype (subthreshold), 0.5J led to significant changes for one or more phenotypes (threshold), and 0.6 and 0.7J resulted in significant changes in all outcomes assessed (mTBI). We further show that linear head kinematics are the most robust predictors of duration of unconsciousness, severity of neurological deficits, white matter injury, and microgliosis following single TBI. Our data extend the validation of CHIMERA as a biofidelic animal model of DAI and establish working parameters to guide future investigations of the mechanisms underlying axonal pathology and inflammation induced by mechanical trauma.


Assuntos
Axônios/efeitos dos fármacos , Concussão Encefálica/fisiopatologia , Encéfalo/efeitos dos fármacos , Lesão Axonal Difusa/tratamento farmacológico , Animais , Axônios/patologia , Fenômenos Biomecânicos/efeitos dos fármacos , Encéfalo/patologia , Concussão Encefálica/patologia , Concussão Encefálica/terapia , Lesão Axonal Difusa/patologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL
18.
PLoS One ; 11(9): e0162384, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27598782

RESUMO

The apolipoprotein E (APOE) gene is the most highly associated susceptibility locus for late onset Alzheimer's Disease (AD), and augmenting the beneficial physiological functions of apoE is a proposed therapeutic strategy. In a high throughput phenotypic screen for small molecules that enhance apoE secretion from human CCF-STTG1 astrocytoma cells, we show the chrysanthemic ester 82879 robustly increases expressed apoE up to 9.4-fold and secreted apoE up to 6-fold and is associated with increased total cholesterol in conditioned media. Compound 82879 is unique as structural analogues, including pyrethroid esters, show no effect on apoE expression or secretion. 82879 also stimulates liver x receptor (LXR) target genes including ATP binding cassette A1 (ABCA1), LXRα and inducible degrader of low density lipoprotein receptor (IDOL) at both mRNA and protein levels. In particular, the lipid transporter ABCA1 was increased by up to 10.6-fold upon 82879 treatment. The findings from CCF-STTG1 cells were confirmed in primary human astrocytes from three donors, where increased apoE and ABCA1 was observed along with elevated secretion of high-density lipoprotein (HDL)-like apoE particles. Nuclear receptor transactivation assays revealed modest direct LXR agonism by compound 82879, yet 10 µM of 82879 significantly upregulated apoE mRNA in mouse embryonic fibroblasts (MEFs) depleted of both LXRα and LXRß, demonstrating that 82879 can also induce apoE expression independent of LXR transactivation. By contrast, deletion of LXRs in MEFs completely blocked mRNA changes in ABCA1 even at 10 µM of 82879, indicating the ability of 82879 to stimulate ABCA1 expression is entirely dependent on LXR transactivation. Taken together, compound 82879 is a novel chrysanthemic ester capable of modulating apoE secretion as well as apoE-associated lipid metabolic pathways in astrocytes, which is structurally and mechanistically distinct from known LXR agonists.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Apolipoproteínas E/genética , Astrócitos/efeitos dos fármacos , Receptores X do Fígado/genética , Piretrinas/farmacologia , Receptores de LDL/genética , Transportador 1 de Cassete de Ligação de ATP/agonistas , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Apolipoproteínas E/agonistas , Apolipoproteínas E/metabolismo , Astrócitos/citologia , Astrócitos/metabolismo , Linhagem Celular Tumoral , Ésteres , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores X do Fígado/agonistas , Receptores X do Fígado/metabolismo , Camundongos , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Cultura Primária de Células , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de LDL/agonistas , Receptores de LDL/metabolismo , Transdução de Sinais
19.
Curr Opin Lipidol ; 27(3): 225-32, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27149391

RESUMO

PURPOSE OF REVIEW: This article evaluates recent experimental and human evidence regarding the involvement of lipids, lipoproteins, and apolipoproteins in neurodegenerative diseases, and reviews the current literature of the effects of cholesterol-lowering treatment on cognition. RECENT FINDINGS: Plasma levels of traditional lipids and lipoproteins are not consistently associated with risk of dementia even though low plasma levels of apolipoprotein E, through unknown mechanisms, robustly predict future dementia. Experimental evidence suggests neuroprotective roles of several brain and cerebrospinal fluid apolipoproteins. Whether plasma levels of apolipoprotein E, or any other apolipoprotein with possible central nervous system and/or blood-brain barrier functions (apolipoproteins J, A-I, A-II, A-IV, D, C-I, and C-III) may become accessible biomarker components that improve risk prediction for dementia together with genetic risk variants and cardiovascular risk factors remains to be determined. SUMMARY: Apolipoproteins with well established functions in peripheral lipid metabolism may play important roles for brain vascular health and Alzheimer's disease pathophysiology. Experimental work on lipids, lipoproteins, and apolipoproteins in the central nervous system together with robust prospective human studies will help to substantiate the drug target potential of these lipid components.


Assuntos
Encéfalo/metabolismo , Lipídeos/sangue , Animais , Apolipoproteínas/sangue , Apolipoproteínas/metabolismo , Humanos
20.
Neurochem Int ; 96: 46-55, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26939762

RESUMO

BACKGROUND: Significant protease activations have been reported after traumatic brain injury (TBI). These proteases are responsible for cleavage of transmembrane proteins in neurons, glial, and endothelial cells and this results in the release of their extracellular domains (ectodomains). METHODS: Two TBI models were employed here, representing both closed head injury (CHI) and open head injury (OHI). In situ zymography, immunohistochemistry, bright field and confocal microscopy, quantification of immunopositive cells and statistical analysis were applied. RESULTS: We found, using in situ zymography, that gelatinase activity of matrix metalloproteinases (MMP)-2 and MMP-9 was upregulated in cortex of both injury models. Using immunohistochemistry for several MPPs (Matrix metalloproteinases) and ADAMs (disintegrin and metalloproteinases), including MMP-2, -9, ADAM-10, -17, distinct patterns of induction were observed in the two TBI models. In closed head injury, an early increase in protein expression of MMP-2, -9 and ADAM-17 was found as early as 10 min post injury in cortex and peaked at 1 h for all 4 proteases examined. In contrast, after OHI the maximal expression was observed locally neighboring the impact site, at a later time-point, as long as 24 h after the injury for MMP-2 and MMP-9. Confocal microscopy revealed colocalization of the 4 proteases with the neuronal marker NeuN in CHI, but only MMP2 colocalized with NeuN in OHI. CONCLUSIONS: The findings may lead to a trauma-induced therapeutic strategy triggered soon after a primary insult to improve survival and to reduce brain damage following TBI.


Assuntos
Traumatismos Craniocerebrais/enzimologia , Traumatismos Cranianos Fechados/enzimologia , Metaloproteinase 2 da Matriz/fisiologia , Metaloproteinase 9 da Matriz/fisiologia , Proteína ADAM17/fisiologia , Animais , Lesões Encefálicas Traumáticas/enzimologia , Lesões Encefálicas Traumáticas/patologia , Traumatismos Craniocerebrais/patologia , Traumatismos Cranianos Fechados/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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