PET imaging to assess blood-brain barrier function in alzheimers disease

PET 成像评估阿尔茨海默病的血脑屏障功能

• 批准号: 252102222
• 负责人: Professor Dr. Jens Pahnke
• 金额: --
• 依托单位: Translational Neurodegeneration and Neuropathology Lab
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/252102222?language=en
• 关键词: PET; imaging; assess; blood; brain

A major hallmark of Alzheimer¿s disease (AD) is the accumulation of senile plaques containing beta-amyloid in the brain. Several lines of evidence suggest that reduced Abeta clearance from the brain underlies Abeta accumulation. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters that are expressed in endothelial cells of the blood-brain barrier (BBB) may play an important role in excreting Abeta from brain into the blood. A number of studies suggest that P-glycoprotein (ABCB1) function at the BBB may be impaired in AD patients as compared with age-matched control subjects. Our own data obtained in amyloid precursor protein (APP) transgenic mice (APPtg) that lack the multidrug resistance protein 1 (ABCC1; APPtg x ABCC1-/-) suggest that ABCC1 may play a more important role than ABCB1 in mediating Abeta clearance from the brain as reflected by up to 14-fold increased Abeta levels in brains of APPtg x ABCC1-/- mice as compared with control mice expressing ABCC1. Moreover, chronic treatment of APPtg mice with thiethylperazine, an antiemetic drug which activates ABCC1 transport activity in vitro, resulted in significant reductions in Abeta load as compared with untreated control animals. However, so far it is not known if ABCC1 function at the BBB is indeed altered during the progression of AD and if treatment with thiethylperazine indeed increases the function of ABCC1 at the BBB. To answer these important questions we will directly measure the functional activity of ABCC1 in vivo at the BBB of AD mouse models using positron emission tomography (PET) and the newly developed radiotracer [18F]BFEP. In addition, Abeta load in mouse brains will be assessed with [11C] Pittsburgh compound B ([11C] PIB) to establish a correlation between regional ABCC1 function and Abeta load in brains of APPtg mice. Using this experimental approach we will investigate the time course of ABCC1 function decline in AD mouse brain and study the effect of thiethylperazine treatment on ABCC1 function. In vivo PET experiments will be complemented with comprehensive immunohistochemistry (IHC) analyses of pathological markers, ABCC1 and Abeta as well as Western blot analysis. We hypothesize that ABCC1 function is decreased in AD mice and that there is an inverse relationship between regional brain Abeta load and ABCC1 function. Pharmacological induction of ABCC1 activity at the BBB may represent an interesting future therapeutic strategy in AD and PET imaging of cerebral ABCC1 function may be a very useful imaging biomarker in the development of such new therapeutics as well as in early diagnosis of AD.

阿尔茨海默病（AD）的一个主要标志是大脑中含有β -淀粉样蛋白的老年斑的积累。几条线索的证据表明，大脑中β清除的减少是β积累的基础。三磷酸腺苷（ATP）结合盒（ABC）转运蛋白在血脑屏障（BBB）内皮细胞中表达，可能在Abeta从脑分泌到血液中起重要作用。许多研究表明，与年龄匹配的对照组相比，AD患者血脑屏障的p -糖蛋白（ABCB1）功能可能受损。我们在缺乏多药耐药蛋白1 （ABCC1; APPtg x ABCC1-/-）的淀粉样前体蛋白（APP）转基因小鼠（APPtg）中获得的数据表明，ABCC1可能比ABCB1在介导大脑中Abeta清除方面发挥更重要的作用，这反映在与表达ABCC1的对照小鼠相比，APPtg x ABCC1-/-小鼠大脑中Abeta水平增加了14倍。此外，与未治疗的对照动物相比，用噻乙基拉嗪（一种在体外激活ABCC1转运活性的止吐药物）慢性治疗APPtg小鼠，导致ABCC1负荷显著减少。然而，到目前为止，尚不清楚ABCC1在血脑屏障的功能是否在AD的进展过程中确实被改变，以及用噻乙基拉嗪治疗是否确实增加了ABCC1在血脑屏障的功能。为了回答这些重要的问题，我们将使用正电子发射断层扫描（PET）和新开发的放射性示踪剂[18F]BFEP直接测量AD小鼠模型血脑屏障处ABCC1的功能活性。此外，我们将用[11C] Pittsburgh化合物B （[11C] PIB）评估小鼠脑内的β负荷，以建立APPtg小鼠脑内ABCC1区域功能与β负荷之间的相关性。我们将通过该实验方法研究AD小鼠脑ABCC1功能下降的时间过程，并研究噻乙基拉嗪治疗对ABCC1功能的影响。体内PET实验将辅以全面的免疫组织化学（IHC）分析病理标志物，ABCC1和Abeta以及Western blot分析。我们假设ABCC1功能在AD小鼠中下降，并且脑区域ABCC1负荷与ABCC1功能之间存在反比关系。血脑屏障ABCC1活性的药理诱导可能代表了AD的一种有趣的未来治疗策略，而脑ABCC1功能的PET成像可能是开发此类新疗法以及AD早期诊断中非常有用的成像生物标志物。

项目成果

Improved method for cannula fixation for long-term intracerebral brain infusion

长期脑内输注插管固定方法的改进

• DOI: 10.1016/j.jneumeth.2017.07.026
• 发表时间: 2017
• 期刊: Journal of Neuroscience Methods
• 影响因子: 3
• 作者: Sike Á;Wengenroth J;Upīte J;Brüning T;Eiriz I;Sántha P;Biverstål H;Jansone B;Haugen HJ;Krohn M;Pahnke J
• 通讯作者: Pahnke J

Morphometric analysis of the cerebral expression of ATP-binding cassette transporter protein ABCB1 in chronic schizophrenia: Circumscribed deficits in the habenula

• DOI: 10.1016/j.schres.2016.02.036
• 发表时间: 2016-11-01
• 期刊: SCHIZOPHRENIA RESEARCH
• 影响因子: 4.5
• 作者: Bernstein, Hans-Gert;Hildebrandt, Jens;Pahnke, Jens
• 通讯作者: Pahnke, Jens