Accelerating Treatment Development for Psychosis in AD: MODEL-AD+P

加速AD精神病的治疗进展：AD+P模式 约40%-60%的阿尔茨海默病患者(AD伴精神病， AD+P)。大量研究发现，AD+P表型与更快的认知能力有关 比无精神病的AD受试者(AD-P)下降。目前，经验性开发的精神病治疗方法 AD的疗效有限，不能改变较快的疾病进展，并与实质性 毒性，包括过高的死亡率。这次更新的目标是弥合知识中的几个关键差距， 目前抑制AD精神病的有效治疗进展：神经生物学特征的描绘 区分AD+P和AD-P；识别逆转这一特征的药物；以及；开发 构建和面对AD+P的有效模型来评价这些药物。 我们希望通过在本供资期间取得的一系列成就的基础上实现这一目标， 其中，我们：1)在SUMF1中确定了AD+P风险的全基因组显著基因座，并发现SUMF1降低 AD+P兴奋性神经元的mRNA表达；2)证实AD+P与过量的磷酸盐有关 负担和新发现AD+P与额叶背外侧皮质过度丢失有关 与AD-P相关的谷氨酸能神经元；3)显示AD+P(相对于AD-P)进一步表现为 突触后密度(PSD)产量降低和PSD蛋白的严重丢失超过谷氨酸的丢失 神经元；4)表征AD+P相对于AD-P的PSD蛋白特征，发现a水平降低 蛋白激酶网络和肌动蛋白细胞骨架的调节器，以及；5)产生计算 预测可能逆转AD+P的PSD蛋白特征的药物。 我们现在将进行一系列综合实验，目的是：1)更精细地解析信令 通过对AD+P的PSD磷酸蛋白质组和动态组特征的研究，AD+P的改变；目的2 计算机识别药物对小鼠PSD蛋白和磷蛋白信号的影响 AD病理模型；目的3)降低小鼠AD病理模型中SUMF1的表达 如果这种手法概括了阿尔茨海默病的神经生物学，并因此可以作为一种结构和 在未来的药理学研究中评估预测有效性的FACE有效模型。 如果成功，我们将更好地表征AD+P的PSD生物学，验证了几个 可用药物作为潜在的新的治疗候选药物，并建立了第一个结构和面临的有效 药物检测的AD+P模式。我们还将与更大的研究团体分享关于 AD+/-P、正常老年人、多种AD小鼠模型和药物的PSD蛋白质组和磷酸蛋白质组 治疗。这些结果将有助于加速AD+P的实验疗法的发展。

Accelerating Treatment Development for Psychosis in AD: MODEL AD+P Psychotic symptoms occur in ~ 40-60% of individuals with Alzheimer Disease (AD with psychosis, AD+P). Numerous studies have found that the AD+P phenotype is associated with more rapid cognitive decline than AD subjects without psychosis (AD-P). Current, empirically developed treatments for psychosis in AD have limited efficacy, do not alter the more rapid disease progression, and are associated with substantial toxicity, including excess mortality. The goal of this renewal is to close several critical gaps in knowledge that currently inhibit effective treatment development for psychosis in AD: delineation of the neurobiologic signature distinguishing AD+P from AD-P; identification of drugs that reverse this signature, and; development of construct and face valid models of AD+P in which to evaluate these drugs. We look to achieve this goal by building on a series of accomplishments from the current funding period, in which we: 1) Identified a genome-wide significant locus for AD+P risk in SUMF1 and found reduced SUMF1 mRNA expression in excitatory neurons in AD+P; 2) Confirmed associations of AD+P with excess phosphotau burden and newly demonstrated that AD+P is associated with excess loss of dorsolateral prefrontal cortex glutamatergic neurons relative to AD-P; 3) Showed that AD+P (relative to AD-P) is further characterized by reduced postsynaptic density (PSD) yield and profound loss of PSD proteins exceeding the loss of glutamate neurons; 4) Characterized the PSD protein signature of AD+P relative to AD-P, finding reduced levels of a network of protein kinases and regulators of the actin cytoskeleton, and; 5) Generated computational predictions of drugs that may reverse the PSD protein signature of AD+P. We will now conduct a set of integrated experiments that will: Aim 1) more finely resolve signaling alterations in AD+P by characterizing the PSD phosphoproteome and kinome signature of AD+P; Aim 2) test computationally identified drugs for effects on the PSD protein and phosophoprotein signature in mouse models of AD pathology, and; Aim 3) reduce SUMF1 expression in mouse models of AD pathology to evaluate if this manipulation recapitulates the neurobiology of psychosis in AD and could thus serve as a construct and face valid model to evaluate for predictive validity in future pharmacological studies. If successful, we will have more finely characterized the PSD biology of AD+P, validated several available drugs as potential novel treatment candidates, and established the first construct and face valid model of AD+P for drug testing. We will also share with the larger research community extensive data on the PSD proteome and phosphoproteome of: AD+/-P, normal elderly, multiple mouse models of AD, and drug treatments. These outcomes will help accelerate development of experimental therapeutics for AD+P.