Therapeutic targeting of TREM2 for Alzheimer's disease
TREM2 治疗阿尔茨海默病的靶向治疗
基本信息
- 批准号:9423846
- 负责人:
- 金额:$ 187.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:APP-PS1Abeta clearanceAcuteAdverse eventAlzheimer&aposs DiseaseAmyloidAmyloid beta-ProteinAmyloid depositionAntibodiesBiochemistryCell SeparationCerebral Amyloid AngiopathyChronicClinicCognitionCognitiveComorbidityDepositionDiseaseDisease PathwayGenesGenetic Population StudyGenetic studyGoalsHistologyHyperhomocysteinemiaImageImmuneImmunohistochemistryImmunologic ReceptorsImmunotherapyImpairmentInflammatory ResponseInnate Immune SystemMagnetic Resonance ImagingMediatingMethodsMicrogliaModelingMusMyeloid CellsNamesNerve DegenerationNeurofibrillary TanglesPathologyPhagocytosisRiskSignal TransductionTREM2 geneTYROBP geneTauopathiesTestingTg2576TherapeuticTimeTransgenic MiceTranslationsVascular Cognitive Impairmentagedamyloid pathologybasebehavior testcerebrovascularcerebrovascular pathologydesigneffective therapygenome wide association studyimmunoregulationimprovedintraperitonealloss of functionmouse modelnano-stringneuroinflammationneuroprotectionnew therapeutic targetnovelpre-clinicalpreventreceptorresponserisk varianttargeted treatmenttau Proteinstherapeutic targetvasogenic edema
项目摘要
ABSTRACT
The identification of novel therapeutic targets for Alzheimer's disease is necessary to reach the goal of the
National Alzheimer's Project Act (NAPA) of having an effective treatment in place by 2025. Despite numerous
promising therapeutic approaches identified pre-clinically to treat Alzheimer's disease, the translation of these
therapies to the clinic have been incredibly disappointing. The vast number of population genetic studies that
have been performed for AD present an opportunity to identify disease pathways what could be targeted
therapeutically. One gene that has a strong effect on AD risk is the triggering receptor expressed on myeloid
cells-2 (TREM2). As the name implies, TREM2, is an innate immune receptor expressed on microglia, known
to signal through DAP12 to trigger phagocytosis. TREM2 SNPs have been identified as significantly increasing
risk of AD in GWAS studies. The hypothesis for this increased risk is that there is a loss of function, impairing
the innate immune system to clear amyloid deposition efficiently. We hypothesize that targeting TREM2 to
activate the receptor will modulate the neuroinflammatory response and stimulate microglia to
phagocytose and clear the amyloid deposits. Furthermore, we hypothesize that activating the TREM2
receptor to modulate the neuroinflammatory response will ameliorate tau pathology, provide
neuroprotection, and avoid cerebrovascular adverse events associated with Aβ targeted therapies. To
activate the TREM2 receptor, we are using an antibody developed by Alector, LLC, Alector-002a, that
recognizes TREM2 and activates the receptor. We have found that the antibody show immune modulation,
clearance of amyloid deposits, and cognitive improvement in amyloid depositing mice. We propose three
specific aims to test our hypothesis:
Specific Aim 1: Determine the neuroinflammatory, amyloid lowering and cognitive effects of A-002a.
Specific Aim 2: Determine the tau modifying, neuroprotective and cognitive effects of A-002a.
Specific Aim 3: Determine the potential for cerebrovascular adverse events of A-002a.
摘要
阿尔茨海默病的新的治疗靶点的鉴定是必要的,以达到本发明的目标。
国家阿尔茨海默病项目法案(NAPA)到2025年有一个有效的治疗方法。尽管多次
有前途的治疗方法确定临床前治疗阿尔茨海默病,这些翻译
临床上的治疗方法令人非常失望。大量的人口遗传学研究,
为确定可能靶向的疾病途径提供了机会
治疗上一个对AD风险有很大影响的基因是髓样细胞表达的触发受体,
细胞-2(TREM 2)。顾名思义,TREM 2是一种在小胶质细胞上表达的先天性免疫受体,已知其在小胶质细胞上表达。
通过DAP 12发出信号以触发吞噬作用。TREM 2 SNP已被鉴定为显著增加
GWAS研究中的AD风险。这种风险增加的假设是功能丧失,
先天免疫系统有效清除淀粉样蛋白沉积。我们假设靶向TREM 2,
激活受体将调节神经炎症反应并刺激小胶质细胞,
吞噬并清除淀粉样沉积物。此外,我们假设激活TREM 2
调节神经炎症反应的受体将改善tau病理,
神经保护,并避免与Aβ靶向治疗相关的脑血管不良事件。到
激活TREM 2受体,我们使用Alector,LLC开发的抗体Alector-002 a,
识别TREM 2并激活受体。我们发现该抗体具有免疫调节作用,
淀粉样蛋白沉积物的清除和淀粉样蛋白沉积小鼠的认知改善。我们提出了三
具体目的是检验我们的假设:
具体目的1:确定A-002 a的神经炎症、淀粉样蛋白降低和认知作用。
具体目的2:确定A-002 a的tau修饰、神经保护和认知作用。
具体目的3:确定A-002 a发生脑血管不良事件的可能性。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Donna M Wilcock其他文献
Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage
- DOI:
10.1186/1742-2094-1-24 - 发表时间:
2004-01-01 - 期刊:
- 影响因子:10.100
- 作者:
Donna M Wilcock;Amyn Rojiani;Arnon Rosenthal;Sangeetha Subbarao;Melissa J Freeman;Marcia N Gordon;Dave Morgan - 通讯作者:
Dave Morgan
Donna M Wilcock的其他文献
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{{ truncateString('Donna M Wilcock', 18)}}的其他基金
Elucidating the role of placental growth factor in diffuse white matter disease
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10607620 - 财政年份:2022
- 资助金额:
$ 187.83万 - 项目类别:
Core F: University of Kentucky Alzheimer's Disease Core Center
核心F:肯塔基大学阿尔茨海默病核心中心
- 批准号:
10261967 - 财政年份:2021
- 资助金额:
$ 187.83万 - 项目类别:
Core F: University of Kentucky Alzheimer's Disease Core Center
核心F:肯塔基大学阿尔茨海默病核心中心
- 批准号:
10459471 - 财政年份:2021
- 资助金额:
$ 187.83万 - 项目类别:
Core F: University of Kentucky Alzheimer's Disease Core Center
核心F:肯塔基大学阿尔茨海默病核心中心
- 批准号:
10662361 - 财政年份:2021
- 资助金额:
$ 187.83万 - 项目类别:
Elucidating the role of placental growth factor in diffuse white matter disease
阐明胎盘生长因子在弥漫性白质疾病中的作用
- 批准号:
10133181 - 财政年份:2020
- 资助金额:
$ 187.83万 - 项目类别:
Elucidating the role of placental growth factor in diffuse white matter disease
阐明胎盘生长因子在弥漫性白质疾病中的作用
- 批准号:
10379950 - 财政年份:2020
- 资助金额:
$ 187.83万 - 项目类别:
Elucidating the role of placental growth factor in diffuse white matter disease
阐明胎盘生长因子在弥漫性白质疾病中的作用
- 批准号:
10597648 - 财政年份:2020
- 资助金额:
$ 187.83万 - 项目类别:
Neurovascular astrocyte dysfunction in VCID
VCID 中的神经血管星形胶质细胞功能障碍
- 批准号:
9306465 - 财政年份:2017
- 资助金额:
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Neurovascular astrocyte dysfunction in VCID
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- 批准号:
10183340 - 财政年份:2017
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