Krivinko Josh M, Erickson Susan L, Abrahamson Eric E, Wills Zachary P, Ikonomovic Milos D, Penzes Peter, Sweet Robert A
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Neurobiol Aging. 2017 Jun;54:59-70. doi: 10.1016/j.neurobiolaging.2017.02.006. Epub 2017 Feb 16.
Psychosis in Alzheimer's disease (AD+P) represents a distinct clinical and neurobiological AD phenotype and is associated with more rapid cognitive decline, higher rates of abnormal behaviors, and increased caregiver burden compared with AD without psychosis. On a molecular level, AD+P is associated with greater reductions in the protein kalirin, a guanine exchange factor which has also been linked to the psychotic disease, schizophrenia. In this study, we sought to determine the molecular and behavioral consequences of kalirin reduction in APPswe/PSEN1dE9 mice. We evaluated mice with and without kalirin reduction during tasks measuring psychosis-associated behaviors and spatial memory. We found that kalirin reduction in APPswe/PSEN1dE9 mice significantly attenuated psychosis-associated behavior at 12 months of age without changing spatial memory performance. The 12-month-old APPswe/PSEN1dE9 mice with reduced kalirin levels also had increased levels of the active, phosphorylated forms of p21 protein (Cdc42/Rac)-activated kinases (PAKs), which function in signaling pathways for maintenance of dendritic spine density, morphology, and function.
阿尔茨海默病伴精神病（AD+P）代表一种独特的临床和神经生物学AD表型，与无精神病的AD相比，其认知衰退更快、异常行为发生率更高，且照料者负担加重。在分子水平上，AD+P与鸟嘌呤交换因子卡里林蛋白的更大程度减少有关，该蛋白也与精神病性疾病精神分裂症有关。在本研究中，我们试图确定APPswe/PSEN1dE9小鼠中卡里林减少的分子和行为后果。我们在测量与精神病相关行为和空间记忆的任务中评估了有或没有卡里林减少的小鼠。我们发现，APPswe/PSEN1dE9小鼠中卡里林减少在12个月大时显著减轻了与精神病相关的行为，而不改变空间记忆表现。卡里林水平降低的12个月大的APPswe/PSEN1dE9小鼠，其活性磷酸化形式的p21蛋白（Cdc42/Rac）激活激酶（PAKs）水平也有所升高，这些激酶在维持树突棘密度、形态和功能的信号通路中发挥作用。
