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

加速AD精神病治疗的发展：AD+P模型 精神病症状发生在约40-60%的阿尔茨海默病患者（AD伴精神病， AD+P）。许多研究发现AD+P表型与更快的认知功能相关， 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，不能改变更快的疾病进展，并且与实质性的 毒性，包括过度死亡。这次更新的目标是填补知识方面的几个关键空白， 目前抑制AD精神病的有效治疗开发：神经生物学特征的描述 区分AD+P和AD-P;鉴定逆转这种特征的药物;开发 构建并面对有效的AD+P模型，以评估这些药物。 我们希望通过在当前供资期取得的一系列成就的基础上实现这一目标， 其中我们：1）在SUMF 1中鉴定了AD+P风险的全基因组显著位点，并发现SUMF 1降低 AD+P中兴奋性神经元的mRNA表达; 2）证实AD+P与过量磷酸化tau蛋白相关 AD+P与背外侧前额叶皮层的过度丢失有关， AD+P（相对于AD-P）的特征还在于： 突触后密度（PSD）产量降低，PSD蛋白的严重损失超过谷氨酸的损失 4）表征AD+P相对于AD-P的PSD蛋白特征，发现AD+P的PSD蛋白水平降低。 肌动蛋白细胞骨架的蛋白激酶和调节剂的网络，以及; 5）生成的计算 可以逆转AD+ P的PSD蛋白特征的药物的预测。 我们现在将进行一系列综合实验，目的是：1）更精细地解析信号 通过表征AD +P的PSD磷酸化蛋白质组和激酶组特征来改变AD+ P; Aim 2）测试 计算鉴定药物对小鼠PSD蛋白和磷蛋白特征的影响 目的3）降低AD病理学小鼠模型中SUMF 1的表达，以评估 如果这种操作概括了AD中精神病的神经生物学，并因此可以作为一种结构， 面对有效的模型，以评估在未来的药理学研究的预测有效性。 如果成功，我们将更精细地表征AD+P的PSD生物学，验证几个 现有的药物作为潜在的新的治疗候选人，并建立了第一个结构和脸有效 用于药物测试的AD+P模型。我们还将与更大的研究社区分享有关 AD+/-P、正常老年人、多种AD小鼠模型和药物的PSD蛋白质组和磷酸化蛋白质组 治疗。这些结果将有助于加速AD+ P实验疗法的开发。

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.