垂体腺苷酸环化酶激活肽在阿尔茨海默病中的研究

Alzheimer’s disease (AD) is the most common cause of dementia in elderly adults. With the growing number of people living to older ages in China, there is an urgency to better understand elements of the pathogenic pathway and establish their roles in early diagnosis and treatment of AD. Pituitary adenylate cyclase activating polypeptide (PACAP) is such a candidate. PACAP is broadly recognized as a potent neurotrophic and neuroprotective peptide. We have found a reduction of both PACAP mRNA transcription and protein expression in AD brains compared to age- and education-matched controls. PACAP levels in the cerebrospinal fluid (CSF) were correlated with these in the brain and were also decreased in AD versus controls. Furthermore, PACAP expression was inversely associated with both pathological hallmarks of AD, i.e. the amyloid plaque burden and neurofibrillary tangles. Since PACAP is reduced in the pathognomonic cortical regions of AD, our findings demonstrate that early detection of reduced PACAP levels in the CSF may be indicative of AD pathology in patients with mild cognitive impairment (MCI) and in those with an increased risk of developing AD. Since CSF collection is difficult and expensive in clinical practice, we propose to use blood samples to.measure PACAP levels in this proposal. We hypothesize that significant changes in PACAP levels can be detected in MCI patients and predict conversion to AD. We will study it step-by-step: 1) To examine whether blood PACAP levels differ between NC, MCI and AD subjects. 2) To examine whether longitudinal changes in blood PACAP levels correlate with conversion from MCI to AD. 3) To examine the specificity of PACAP in other neurodegenerative conditions. 4) To examine the cause-effect relationship of PACAP and AD pathology in a transgenic animal model.of AD to further explore its therapeutic potential.

阿尔茨海默病（AD）是严重威胁老年人生命健康的主要疾病之一。随着越来越多的人进入老年阶段，我们迫切需要建立有效的早期诊断和治疗方法。垂体腺苷酸环化酶激活多肽（PACAP）是一种强效的神经营养肽类。我们前期研究发现与健康人群相比AD病人脑内PACAP的信使核糖核酸及蛋白水平均下调，其下调主要出现于发病累及的病区。而且PACAP的表达与AD的病理特征（淀粉样蛋白板块和神经纤维缠结）呈负相关。脑脊液中PACAP减少的水平可以早期检测轻度认知障碍，但是脑脊液的收集既困难又昂贵，因此我们将使用血液用品以测量PACAP的水平。到目前为止，世界上还没有任何一种血液样品可以用于诊断AD。我们的研究将会填补这一空缺。在本申请中我们将从临床入手定量检测健康对照、轻度认知障碍及AD患者血液样本中PACAP的横向和纵向变化，并且结合动物模型研究PACAP与AD发病的因果关系并且进一步探讨其治疗潜力。

垂体腺苷酸环化酶激活多肽(Pituitary adenylate cyclase-activating polypeptide, PACAP）是一种强效的具有神经营养性和神经保护性作用的肽类。PACAP通过下游的Sirtuin 3（Sirt3）蛋白进一步发挥神经保护作用。在研究过程，关注PACAP及下游的Sirt3与阿尔茨海默病（Alzheimer‘s Disease，AD）有关的病理机制，通过在AD小鼠模型及恒河猴动物模型上验证，进一步明确了PACAP及Sirt3与衰老、认知功能和AD典型病理之间的相关性。.研究发现了PACAP水平，衰老，认知功能和淀粉样蛋白负荷在非人灵长类动物之间的关联。另外，Sirt3作为PACAP下游主要调控指标，在AD的转基因小鼠模型（APPSwInd）的皮质神经元，发现Sirt3在调节淀粉样蛋白（Amyloid-β，Aβ）诱导的脑代谢减退中起重要作用。此外，在人群中，发现AD受试者的内嗅皮质，颞中回和额上回的Sirt3水平降低，且与较差的认知水平以及tau病理学的严重性相关。通过在动物模型中进一步验证其机制关系，发现Sirt3可以调节淀粉样蛋白以及tau蛋白磷酸化。而Sirt3敲低可减少人ApoE3初级神经元的耗氧量和ATP产生， Sirt3过表达可保护ApoE4神经元的这些损伤。.这一发现进一步验证了PACAP与AD病理发生机制中更深的关系，同时也验证了Sirt3与AD病理的相关性。为我们提供了早期诊断的新的可能的生物学标志物，这进一步说明了Sirt3也是潜在的治疗和预防AD的新型治疗靶标，为将来的临床转化研究提供了新的方向。