Cortical Synapses and Psychosis in AD

精神病发生在40-60%的阿尔茨海默病（AD）受试者中，并导致治疗费用增加。 照顾患有AD的退伍军人目前使用类似药物治疗AD精神病的努力 没有痴呆症的患者的症状在很大程度上是失败的，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， 遗传率为61%。目前的遗传数据支持一种模型，即增加AD风险的遗传变异 在患有或不患有精神病的AD受试者中同样如此。其他变异增加了精神病的风险， 视AD的发展而定，早期至中期精神病发作增加最快， AD的阶段。AD中精神病的遗传变异与AD中导致精神病风险的遗传变异重叠。 精神分裂症大量研究发现，AD伴精神病（AD+P）受试者的脑组织中， 认知功能下降，精神病发作前，比AD患者无精神病（AD-P）。因为synapse 丧失是AD中认知下降的最强相关性，因此更大的突触丧失可能是AD中 AD+P表型。新出现的AD图片表明，树突棘及其突触的丢失是AD的一个重要原因。 由可溶性寡聚淀粉样蛋白β（A？）驱动。可溶性A引起的脊柱丢失取决于 磷酸化Tau（pTau）并参与突触可塑性的分子介质，导致谷氨酸耗尽 受体（GluR，NMDAR）从突触后密度（PSD）。在最初的融资期间，我们 评估了AD-P和AD+P受试者的脑中kalirin蛋白（RAC/Rho鸟嘌呤核苷酸交换）水平 在树突棘的维持和生长中起关键作用的因子。这些财产和卡利林的证据 与精神分裂症的精神病风险相关，使其成为AD精神病的强有力候选分子。在 在AD+ P中，Braak 3-5期受试者、kalirin-9和kalirin-12选择性降低。 在AD + P和AD+P中均存在，但在AD+ P中明显加速。 可溶性A <$1 -42：A <$1 -40比率在这些阶段中在AD+P和AD-P受试者之间没有差异。但 一些关键问题仍然存在。Kalirin-7、Kalirin-9和Kalirin-12存在于PSD级分中，然而，Kalirin-9和Kalirin-12存在于PSD级分中。 在其他区室中显著表达。因此，确定哪些同种型有助于病理学， AD+P需要评估隔室特异性表达。虽然已知减少卡林会消耗 PSD GluR 1，NMDAR 2B，并导致脊柱损失，目前尚不清楚是否减少卡林加速这些影响， 增加可溶性A？。相反，我们和其他人已经表明，增加kalirin的表达- 7和-9增加脊柱密度。然而，增加kalirin表达是否可以保护免受A？ 引起的脊柱缺失也是未知的。我们现在建议通过结合人体组织 在动物和体外模型中检查因果关系的研究：1. AD+P和AD-P中卡林亚型的水平; 2.为了比较突触后谷氨酸受体的水平， AD+P和AD-P; 3.以确定是否减少卡林增强A引起的脊柱损失。拟议的研究 在他们对AD+P表型的关注方面具有高度创新性，这是临床上重要的，可遗传的，并赋予 更快的进展过程的倾向，从而提供了一种新的方法来发现疾病 修改机制。方法上的创新包括：使用了由 我们的顾问，Penzes博士;将kalirin小鼠与PSAPP模型的A？过度生产，以及;使用 LC-SRM/MS定量。建议研究的结果将为未来的研究提供基础 评估卡利林下游的特定途径，以及是否进行体内干预以增加卡利林 信号传导可以防止或逆转A？诱导的脊髓损伤。最终，阐明这些机制 可能导致AD+ P退伍军人的认知和行为益处。

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.