Vascular cognitive impairment in hypertension; identification of an age appropriate model.

摘要 预计痴呆症患者的人数将在30年内达到流行病的比例。 脑血管疾病会导致一系列特定的认知障碍， 轻度血管性认知障碍（VCI）至改变生命的血管性痴呆（VaD）。VaD是第二大 阿尔茨海默病（AD）后常见的痴呆类型。VaD仅存在于5 - 10%的痴呆病例中， 更常与包括AD在内的其他痴呆一起出现并加重。这就提出了一种可能性， 脑脉管系统是减缓或阻止痴呆发展的治疗靶点。功能性大脑 动脉对于营养和氧气的输送至关重要，它们也可以作为一个管道， 神经保护/恢复药物递送。任何潜在的痴呆症治疗都需要进行临床前研究。 在适当的动物模型中进行测试，但VaD模型的可用性令人惊讶地有限; 这将填补这一知识空白。强有力的证据将中年高血压与以后的痴呆症发展联系起来 生活中这种联系可能是高血压相关的血管功能损害和慢性炎症的结果。 脑灌注不足许多信号通路已被确定为介导的影响， 脑动脉高血压目前尚不清楚这些途径如何转化为人类，因为大多数 这些研究使用了年轻的动物;这些模型没有考虑到高血压和衰老的综合影响。 为了确定和验证治疗靶点，我们必须适当地模拟疾病进展;这 要求高血压开始要到中年。一种新的高血压模型已经开发出来 可以用来概括人群中高血压发展的时间进程。在这个模型中， 专门由设计者药物激活的设计者受体（DREADD）用于诱导 醛固酮增多症和高血压。AS +/Cre hM3Dq小鼠特异性表达Gq偶联的DREADD， 肾上腺皮质，其中受体活化诱导醛固酮合酶表达，导致原发性 醛固酮增多症我们的中心假设是AS +/Cre hM3Dq小鼠将是一个有用的模型VCI/VaD， 适当地反映了老龄化人口及其痴呆相关的共病。在目标1中，我们将评估 氯氮平激活DREADD后AS +/Cre hM3Dq小鼠高血压发生 被推迟到中年。目标2和3将利用行为测试和分子方法来评估认知能力。 功能我们知道，衰老和高血压分别损害脑动脉功能;我们不知道是否 两个条件具有累加效应。拟议的研究将为该领域提供一个可行的模型， VaD潜在疗法的临床前试验。这个模型也将允许阐明的机制， 将高血压与脑小血管功能障碍和认知能力下降联系起来。 这可能导致高血压相关VaD的新的治疗靶点的确定。

Abstract The number of patients suffering from dementia is expected to reach epidemic proportions within 30 years. Cerebrovascular disease leads to the development of a specific spectrum of cognitive disorders that range from mild vascular cognitive impairment (VCI) to life altering vascular dementia (VaD). VaD is the second most common type of dementia following Alzheimer’s disease (AD). VaD exists lone in 5-10% of dementia cases, but more commonly appears with, and exacerbates, other dementias including AD. This presents the possibility that the cerebral vasculature is a therapeutic target to slow or stop the development of dementia. Functional cerebral arteries are crucial for nutrient and oxygen delivery, and they could also serve as a conduit for neuroprotective/restorative drug delivery. Any potential dementia treatment will need to undergo preclinical testing in appropriate animal models but the availability of models for VaD is surprisingly limited; the studies proposed will fill this knowledge gap. Strong evidence links midlife hypertension to dementia development later in life. This connection is likely the result of hypertension associated impairments in vascular function and chronic cerebral hypoperfusion. Many signaling pathways have been identified as mediators of the effects of hypertension on cerebral arteries. It is not clear how well these pathways translate to humans because most studies utilized young animals; these models do not account for the combined effects of hypertension and aging. To identify and validate therapeutic targets it is vital that we model that disease progression appropriately; this requires that hypertension does not begin until middle-age. A new model of hypertension has been developed that could be used to recapitulate the time course of hypertension development in the population. In this model, designer receptors exclusively activated by designer drugs (DREADDs) are utilized to induce hyperaldosteronism and hypertension. The AS+/Cre hM3Dq mice express the Gq-coupled DREADD specifically in the adrenal cortex, where receptor activation induces aldosterone synthase expression resulting in primary hyperaldosteronism. Our central hypothesis is that the AS+/Cre hM3Dq mice will be a useful model VCI/VaD that appropriately reflects the aging population and their dementia related co-morbidities. In aim 1 we will evaluate the development of hypertension in AS+/Cre hM3Dq mice when DREADD activation with clozapine N-oxide (CNO) is delayed until middle-age. Aims 2 and 3 will utilize behavioral testing and molecular methods to assess cognitive function. We know that aging and hypertension individually impair cerebral artery function; we do not know if the two conditions have an additive effect. The proposed studies will provide the field with a viable model for preclinical testing of potential therapies for VaD. This model will also allow for the elucidation of the mechanisms linking hypertension to cerebral small vessel dysfunction and cognitive decline in an age appropriate manner. This could lead to the identification of novel therapeutic targets for hypertension associated VaD.