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

摘要 痴呆症患者的数量预计将在30年内达到流行比例。 脑血管疾病导致一系列特定的认知障碍的发展，范围从 从轻微的血管认知障碍(VCI)到改变生活的血管性痴呆(VAD)。VAD是第二大 阿尔茨海默病(AD)后的常见痴呆症。在5%-10%的痴呆症患者中，VAD是单独存在的，但 更常与包括阿尔茨海默病在内的其他痴呆一起出现，并使其恶化。这提出了一种可能性： 脑血管是延缓或阻止痴呆症发展的治疗靶点。功能性脑 动脉对于营养和氧气的输送是至关重要的，它们也可以作为 神经保护/恢复性药物输送。任何潜在的痴呆症治疗都需要进行临床前治疗。 在适当的动物模型中进行试验，但vad模型的可用性令人惊讶地有限；这些研究 提议将填补这一知识空白。强有力的证据表明，中年高血压与以后的痴呆症发展有关 在生活中。这种联系可能是高血压相关的血管功能损害和慢性 脑低灌注症。许多信号通路已被确定为影响 脑动脉的高血压。目前还不清楚这些途径对人类的影响有多大，因为大多数 研究使用了年轻的动物；这些模型没有考虑高血压和衰老的综合影响。 为了确定和验证治疗目标，至关重要的是我们对疾病进展进行了适当的建模；这 要求高血压在中年之前不会开始。一种新的高血压模型已经被开发出来 这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， 由设计师药物(DREADD)专属激活的设计师受体被用来诱导 醛固酮增多症和高血压。AS+/Cre hM3Dq小鼠特异性表达GQ偶联DREADD 肾上腺皮质，在那里受体激活诱导醛固酮合成酶表达导致原发性 醛固酮过多症。我们的中心假设是AS+/CRE hM3Dq小鼠将是一个有用的VCI/VAD模型， 恰当地反映了人口老龄化及其与痴呆症相关的共病情况。在目标1中，我们将评估 氯氮平激活时AS+/Cre hM3Dq小鼠高血压的发生 被推迟到中年。目标2和目标3将利用行为测试和分子方法来评估认知 功能。我们知道衰老和高血压分别损害大脑动脉功能；我们不知道 有两个条件具有相加效应。拟议的研究将为该领域提供一个可行的模式 VaD潜在治疗方法的临床前试验。这一模型还将有助于阐明这种机制。 以适合年龄的方式将高血压与大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.