Cortical Synapses and Psychosis in AD

描述（由申请人提供）： 精神病发生在40-60%的阿尔茨海默病（AD）受试者中，并导致护理AD退伍军人的成本增加。目前，在没有痴呆的患者中使用类似症状的药物治疗AD中的精神病的努力在很大程度上失败了，可能是因为缺乏生物特异性。重要的是，三个独立的重复研究发现，AD中的精神病是家族性的，估计遗传率为61%。目前的遗传学数据支持一种模型，即增加AD风险的遗传变异在有或无精神病的AD受试者中同样如此。额外的变异增加了精神病的风险，取决于AD的发展，在AD的早期至中期，精神病发作的增加最快。AD中精神病的遗传变异与精神分裂症中精神病风险的遗传变异重叠。大量研究发现，AD伴精神病（AD+P）患者在精神病发作前的认知功能下降速度比AD不伴精神病（AD-P）患者快。由于突触丢失是AD中认知下降的最强相关性，因此更大的突触丢失可能是AD+P表型的基础。新出现的AD图像表明，树突棘及其突触的丢失是由可溶性寡聚淀粉样β（A β）物质驱动的。可溶性A β诱导的棘丢失依赖于磷酸化Tau（pTau），并参与突触可塑性的分子介质，导致突触后密度（PSD）中谷氨酸受体（GluR，NMDAR）的耗尽。在最初的资助间隔期间，我们评估了AD-P和AD+P受试者的kalirin蛋白的脑水平，kalirin蛋白是RAC/Rho鸟嘌呤核苷酸交换因子，在树突棘维持和生长中起关键作用。这些特性以及卡林与精神分裂症中精神病风险相关的证据使其成为AD中精神病的强有力候选分子。在Braak 3-5期受试者中，kalirin-9和kalirin-12在AD+ P中选择性减少。kalirin-7的减少在AD-P和AD+P中都存在，但在AD+ P中明显加速。尽管在这些阶段AD+P和AD-P受试者之间的可溶性A β 1-42：A β 1-40比率没有差异，但这些减少仍然发生。然而，仍然存在一些关键问题。Kalirin-7、Kalirin-9和Kalirin-12在PSD组分中发现，然而，Kalirin-9和Kalirin-12在其他区室中具有显著表达。因此，确定哪些亚型有助于AD+P的病理需要评估区室特异性表达。虽然已知减少kalirin会耗尽PSD GluR 1，NMDAR 2B，并导致脊柱损失，但不知道减少kalirin是否会在可溶性A β增加的情况下加速这些作用。相反，我们和其他人已经表明，kalirin- 7和-9的表达增加会增加棘密度。然而，增加kalirin表达是否可以防止A β诱导的脊柱丢失也是未知的。我们现在建议通过结合人体组织研究和动物及体外模型中因果关系的检查来解决这些问题：1.定量AD+P和AD-P中Kalirin亚型的突触后水平;比较AD+P和AD-P突触后谷氨酸受体的水平; 3.以确定是否减少卡林增强A β诱导的脊柱丢失。拟议的研究是高度创新的，他们专注于AD+P表型，这是临床上重要的，可遗传的，并赋予责任，以更快的进展过程，从而提供了一种新的方法来发现疾病的修改机制。方法创新包括：使用我们的顾问Penzes博士开发的kalirin敲除小鼠;将kalirin小鼠与A β过量生产的PSAPP模型杂交;以及使用LC-SRM/MS定量。拟议研究的结果将为未来评估kalirin下游特定途径的研究提供基础，以及增加kalirin信号传导的体内干预是否可以预防或逆转A β诱导的脊髓损伤。最终，阐明这些机制可能会为AD+ P退伍军人带来认知和行为方面的益处。

DESCRIPTION (provided by applicant): Psychosis occurs in 40-60% of subjects with Alzheimer disease (AD) and contributes to increased costs of caring for Veterans with AD. Current efforts to treat psychosis in AD with medications used for similar symptoms in patients without dementia have largely failed, potentially because of lack of biologic specificity. Importantly, three independent replications have found that psychosis in AD is familial, with an estimated heritability of 61%. Current genetic data support a model in which genetic variants that increase the risk for AD do so equally in AD subjects with or without psychosis. Additional variants increase the risk for psychosis, contingent on the development of AD, with the most rapid increase in onset of psychosis in early to middle stages of AD. The genetic variants for psychosis in AD overlap with those that contribute to psychosis risk in schizophrenia. Numerous studies have found that AD subjects with psychosis (AD+P) have more rapid cognitive decline, preceding psychosis onset, than AD subjects without psychosis (AD-P). Because synapse loss is the strongest correlate of cognitive decline in AD, greater synapse loss is thus likely to underlie the AD+P phenotype. The emerging picture of AD indicates that loss of dendritic spines and their synapses are driven by soluble oligomeric amyloid beta (A�) species. Soluble A�-induced spine loss depends on phosphoTau (pTau) and engages molecular mediators of synaptic plasticity, resulting in depletion of glutamate receptors (GluR, NMDAR) from the post-synaptic density (PSD). During the initial funding interval we evaluated AD-P and AD+P subjects for brain levels of kalirin protein, a RAC/Rho guanine nucleotide exchange factor with critical roles in dendritic spine maintenance and growth. These properties, and evidence of kalirin's association with psychosis risk in schizophrenia, made it a strong candidate molecule for psychosis in AD. In Braak stage 3-5 subjects, kalirin-9, and kalirin-12 were selectively reduced in AD+P. Reductions in kalirin-7 were present in both AD-P and AD+P, but markedly accelerated in AD+P. These reductions occurred despite soluble A�1-42:A�1-40 ratios that did not differ between AD+P and AD-P subjects in these stages. However, a number of critical questions remain. Kalirin-7, -9, and -12 are found in PSD fractions, however, -9 and -12 have significant expression in other compartments. Thus, determining which isoforms contribute to pathology in AD+P requires evaluating compartmental-specific expression. Although kalirin reduction is known to deplete PSD GluR1, NMDAR2B, and cause spine loss, it is not known if reduced kalirin accelerates these effects in the presence of increased soluble A�. Conversely, we and others have shown that increased expression of kalirin- 7 and -9 increases spine density. However, whether increased kalirin expression can protect against A�-induced spine loss is also unknown. We now propose to address these questions by combining human tissue studies with examination of causal relationships in animal and in vitro models: 1.To quantitate post-synaptic levels of kalirin isoforms in AD+P and AD-P; 2. To compare post-synaptic levels of glutamate receptors in AD+P and AD-P; 3. To determine if kalirin reduction enhances A�-induced spine loss. The proposed studies are highly innovative in their focus on the AD+P phenotype which is clinically important, heritable, and confers liability to a more rapidly progressive course, thus providing a novel approach to discovery of disease modifying mechanisms. Methodologic innovations include: the use of the kalirin knockout mouse developed by our consultant, Dr. Penzes; crossing the kalirin mouse with a PSAPP model of A� overproduction, and; the use of LC-SRM/MS quantification. Findings from the proposed studies will provide the basis for future studies assessing the specific pathways downstream of kalirin, and whether in vivo interventions to increase kalirin signaling may prevent or reverse A�-induced impairments in spines. Ultimately, elucidating these mechanisms may lead to cognitive and behavioral benefits for Veterans with AD+P.