Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
基本信息
- 批准号:10043824
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-10-01 至 2023-09-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAffectAgeAge-MonthsAggressive behaviorAgitationAlzheimer&aposs DiseaseAlzheimer&aposs disease careAlzheimer&aposs disease modelAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmericanAnti-Anxiety AgentsAnti-Inflammatory AgentsAntidepressive AgentsAntipsychotic AgentsAnxietyAstrocytesAttenuatedBehaviorBehavioralBehavioral SymptomsBiological MarkersBrainBrain imagingC-reactive proteinCaregiversCaringCause of DeathCharacteristicsChronicClinicalClinical ResearchClinical TrialsConfusionDataDementiaDepositionDevelopmentDirect CostsEmotionalEncephalitisEtiologyExhibitsFamilyFemaleFinancial HardshipGlial Fibrillary Acidic ProteinGoalsGrantHumanImmunofluorescence ImmunologicImmunotherapyIndividualInflammationInflammatoryInjuryInstitutesInterleukin-6Knock-inKnock-in MouseLiteratureMajor Depressive DisorderMeasuresMental DepressionMental disordersMicrogliaModelingMood DisordersMusNADPH OxidaseNeurodegenerative DisordersPathway interactionsPatient CarePatientsPerformancePersonalityPharmaceutical PreparationsPharmacological TreatmentPhenotypePlasmaPost-Traumatic Stress DisordersProcessProductionProgressive DiseasePublishingQuality of lifeRegression AnalysisReportingRiskRoleSchizophreniaSerumSignal TransductionSliceSuperoxide DismutaseSuperoxidesSymptomsTestingTherapeuticUnited StatesVeteransWild Type Mouseacetovanilloneagedassociated symptombasebehavior testdesignfluorescence imaginghypnoticimprovedinflammatory markerinhibitor/antagonistjuvenile animalmalemimeticsmouse modelneuroinflammationneuropsychiatric symptomneuropsychiatryneurotoxicitynonhuman primatenoveloverexpressionpreventpsychiatric symptomrisk stratificationsedativeside effectsmall moleculetreatment effecttreatment strategy
项目摘要
Alzheimer’s disease (AD) affects 1 in 8 Americans, and is the sixth leading cause of death in the United States.
Nearly a quarter of a million of those living with AD are Veterans, and recent studies have shown that Veterans
have a 60% increased risk of developing AD. Behavioral changes, such as agitation and aggression, confusion,
and dramatic personality changes, termed neuropsychiatric symptoms (NPS) are highly prevalent in AD patients,
and are extremely challenging for caregivers, placing significant emotional and financial burdens on those caring
for patients with AD, yet current pharmacological treatments for NPS, such as antipsychotics, sedative/hypnotics,
anxiolytics, and antidepressants, often have significant adverse effects that outweigh the benefits of these
treatments. Thus, it is critical to develop better therapeutic approaches to NPS in AD patients. In the general
psychiatric literature, there is an emerging idea that inflammation may be a critical contributor to the etiology of
psychiatric conditions including mood disorder, major depression, post-traumatic stress disorder (PTSD), and
even schizophrenia. How inflammatory processes contribute to neuropsychiatric symptoms in AD has not yet
been studied. Neuropsychiatric manifestations in AD patients occur in the context of a progressive
neurodegenerative disease – the characteristic of AD - which produces substantial inflammation, itself, so we
believe it is critical to understand the role of inflammation in NPS specifically in the context of AD, the ultimate
goal of this application.
This application is based on the emerging idea that brain inflammation may contribute to psychiatric
conditions including depression, post-traumatic stress disorder (PTSD), and even schizophrenia. We propose
the hypothesis that treating neuroinflammation in AD patients will prevent or decrease neuropsychiatric
symptoms such as agitation, aggression, and apathy, with the potential of finding alternative and better
treatments for Veterans with these difficult-to-treat and often devastating behavioral symptoms of AD.
The premise for this grant is based on the literature, our published data, and new preliminary data, which show
that anti-inflammatory treatment treatments directed at interleukin-6 (IL-6) signaling, specifically, will be effective
in attenuating NPS in relevant models. Aim 1 will ask whether evidence of inflammation predicts increased risk
of NPS in a new mouse model of AD (the hAPP knockin mice recently developed at the Riken Institute) - mice
known to exhibit progressive brain inflammation - and will characterize how aged AD mice perform on behavioral
tasks relevant to human NPS. Markers of inflammation to be correlated with behavior will include serum C-
reactive protein and IL-6, which have been strongly associated with many psychiatric disease states. In addition,
neuroinflammation will be assessed by quantifying the number of activated astrocytes (GFAP) and microglia
(Iba1) using confocal fluorescence imaging of brain slices at three ages: 5, 12, and 18 months. Males and
females will be studied. Aim 2 will test the hypothesis that three anti-inflammatory strategies targeting IL-6 and
downstream signaling will reduce NPS behaviors in these same mice. Treatments will include: siltuximab
(Sylvant), a clinically approved anti-IL-6 immunotherapy; Apocynin, a NADPH oxidase inhibitor; and
Dismutazyme, a small molecule catalytic superoxide dismutase mimetic, shown to be effective in mice and non-
human primates. The goal will be to determine whether these anti-inflammatory treatments prevent or reduce
NPS in AD. Ultimately, if treatments which reduce inflammation in the brain prevent or decrease NPS in AD
patients, this could support development of alternative or adjunct treatments to conventional drugs being used,
thus improving the quality of life and decreasing the burden of NPS in patients living with AD. Finally, results
from this study may suggest that biomarkers of inflammation could be used as predictors of NPS risk, thus
improving risk stratification for clinical studies on NPS in AD.
阿尔茨海默病(AD)影响了八分之一的美国人,是美国第六大死亡原因。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Laura L Dugan其他文献
Mitochondrial Uncoupling Proteins in the Central Nervous System Recommended Citation
中枢神经系统中的线粒体解偶联蛋白推荐引文
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Jeong Sook;Kim;Laura L Dugan;Dugan;Laura L - 通讯作者:
Laura L
Laura L Dugan的其他文献
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{{ truncateString('Laura L Dugan', 18)}}的其他基金
Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
- 批准号:
10514598 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
- 批准号:
9665155 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.
阿尔茨海默病 (AD) 神经精神症状的新疗法:在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。
- 批准号:
10292955 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Inflammatory Mechanisms Underlie Lysosome Failure in the Aging Brain
炎症机制是衰老大脑中溶酶体衰竭的基础
- 批准号:
10159817 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Inflammatory Mechanisms Underlie Lysosome Failure in the Aging Brain
炎症机制是衰老大脑中溶酶体衰竭的基础
- 批准号:
10406349 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Inflammatory Mechanisms Underlie Lysosome Failure in the Aging Brain
炎症机制是衰老大脑中溶酶体衰竭的基础
- 批准号:
9923516 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
- 批准号:
9293672 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
- 批准号:
8113936 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
- 批准号:
8292022 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Systemic Inflammation and Central Nervous System Dysfunction
全身炎症和中枢神经系统功能障碍
- 批准号:
8705765 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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