Cortical Synapses and Psychosis in AD

40%-60%的阿尔茨海默病(AD)患者会出现精神病，并导致 照顾患有AD的退伍军人。目前使用类似药物治疗AD精神病的研究进展 非痴呆症患者的症状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的精神病是家族性的，估计 遗传力为61%。目前的遗传数据支持一种模型，在该模型中，增加AD风险的基因变异 在患有或不患有精神病的AD受试者中也是如此。更多的变异会增加患精神病的风险， 视阿尔茨海默病的发展而定，精神病发病在早至中期增长最快 AD的各个阶段。AD患者精神病的基因变异与导致AD精神病风险的基因变异重叠 精神分裂症。大量研究发现，患有精神病(AD+P)的AD患者具有更快的 认知功能减退，在精神病发作之前，比无精神病的AD受试者(AD-P)更重要。因为Synapse 丢失是阿尔茨海默病认知功能下降的最强相关性，因此更大的突触丢失可能是 AD+P表型。AD的新图像表明，树突棘及其突触的丢失是 由可溶性低聚淀粉样β蛋白(A？)物种驱动。可溶性A？引起的脊柱丢失依赖于 磷酸化Tau(Ptau)和参与突触可塑性的分子介体，导致谷氨酸耗竭 突触后密度(PSD)的受体(Glur、NMDAR)。在最初的融资期间，我们 评估AD-P和AD+P受试者脑中Kalirin蛋白的水平，这是一种RAC/Rho鸟嘌呤核苷酸交换 在树突棘的维持和生长中起关键作用的因子。这些性质以及卡利林的证据 与精神分裂症的精神病风险有关，使其成为阿尔茨海默病的有力候选分子。在……里面 Braak分期3-5的受试者、Kalirin-9和Kalirin-12在AD+P中选择性降低。Kalirin-7的降低 在AD-P和AD+P中都存在，但在AD+P中明显加速。 可溶性A？1-42：A？1-40比率在AD+P和AD-P受试者之间在这些阶段没有差异。然而，a 一些关键问题仍然存在。在PSD组分中发现Kalirin-7、-9和-12，然而-9和-12 在其他隔间有显著的表达。因此，确定哪些亚型对病理有贡献 AD+P需要计算特定于隔间的表达式。尽管已知的加里林减量会耗尽 PSD GluR1、NMDAR2B和导致脊柱丢失，目前尚不清楚减少的Kalirin是否在 存在增加的可溶性A？相反，我们和其他人已经证明，Kalirin的表达增加- 7和-9会增加脊椎密度。然而，增加Kalirin的表达是否可以预防A？ 诱发性脊椎缺失也是未知的。我们现在建议通过结合人体组织来解决这些问题 动物模型和体外模型因果关系检验的研究：1.定量测定突触后 卡利林亚型在AD+P和AD-P中的表达；2.比较大鼠突触后谷氨酸受体水平 AD+P和AD-P；3.确定Kalirin减少是否增强A？引起的脊柱丢失。建议进行的研究 在关注AD+P表型方面具有很高的创新性，这种表型在临床上很重要，可遗传，并具有 倾向于一个更快速发展的过程，从而提供了一种发现疾病的新方法 修改机制。方法上的创新包括：使用由 我们的顾问Penze博士；将Kalirin小鼠与A？生产过剩的PSAPP模型进行杂交，以及；使用 LC-SRM/MS定量。拟议研究的结果将为今后的研究提供基础。 评估Kalirin下游的特定途径，以及体内干预是否增加Kalirin 信号转导可以防止或逆转A？引起的脊椎损伤。最终，阐明这些机制 可能会给患有AD+P的退伍军人带来认知和行为上的好处。

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.