Jimenez Heidy, Adrien Leslie, Wolin Adam, Eun John, Chang Eric H, Burstein Ethan S, Gomar Jesus, Davies Peter, Koppel Jeremy
Northwell Health The Feinstein Institutes for Medical Research Manhasset New York USA.
ACADIA Pharmaceuticals San Diego California USA.
Alzheimers Dement (N Y). 2022 Feb 1;8(1):e12247. doi: 10.1002/trc2.12247. eCollection 2022.
Psychosis in Alzheimer's disease (AD) is associated with grave clinical consequences including a precipitous cognitive decline and a hastened demise. These outcomes are aggravated by use of existing antipsychotic medications, which are also associated with cognitive decline and increased mortality; preclinical models that would develop new therapeutic approaches are desperately needed. The current report evaluates the ability of the neoteric antipsychotic, pimavanserin, to normalize hyperkinesis and sensorimotor gating in the novel catechol--methyltransferase (COMT) deleted P301L/COMT- and rTg(P301L)4510 models of psychotic AD, and the impact of pimavanserin on tau pathology.
Female P301L/COMT- mice were behaviorally characterized for abnormalities of locomotion and sensorimotor gating, and biochemically characterized for patterns of tau phosphorylation relative to relevant controls utilizing high-sensitivity tau enzyme-linked immunosorbent assay (ELISA). Female P301L/COMT- and rTg(P301L)4510 mice were randomized to pimavanserin or vehicle treatment to study the ability of pimavanserin to normalize locomotion and rescue sensorimotor gating. Additionally, high-sensitivity tau ELISA was used to investigate the impact of treatment on tau phosphorylation.
P301L/COMT- mice evidenced a hyperlocomotive phenotype and deficits of sensorimotor gating relative to wild-type mice on the same background, and increased tau phosphorylation relative to COMT-competent P301L mice. Pimavanserin normalized the hyperkinetic phenotype in both the P301L/COMT- and rTg(P301L)4510 mice but had no impact on sensorimotor gating in either model. Pimavanserin treatment had little impact on tau phosphorylation patterns.
These data suggest that pimavanserin ameliorates tau-driven excessive locomotion. Given the morbidity associated with aberrant motor behaviors such as pacing in AD and lack of effective treatments, future studies of the impact of pimavanserin on actigraphy in patients with this syndrome may be warranted.
阿尔茨海默病（AD）中的精神病与严重的临床后果相关，包括认知能力急剧下降和死亡加速。现有抗精神病药物的使用会加剧这些后果，这些药物还与认知能力下降和死亡率增加有关；迫切需要能够开发新治疗方法的临床前模型。本报告评估新型抗精神病药物匹莫范色林使新型儿茶酚 - 甲基转移酶（COMT）缺失的P301L/COMT - 和rTg（P301L）4510精神病性AD模型中的运动亢进和感觉运动门控正常化的能力，以及匹莫范色林对tau病理学的影响。
对雌性P301L/COMT - 小鼠的运动和感觉运动门控异常进行行为学表征，并利用高灵敏度tau酶联免疫吸附测定（ELISA）相对于相关对照对tau磷酸化模式进行生化表征。将雌性P301L/COMT - 和rTg（P301L）4510小鼠随机分为匹莫范色林或赋形剂治疗组，以研究匹莫范色林使运动正常化和挽救感觉运动门控的能力。此外，使用高灵敏度tau ELISA来研究治疗对tau磷酸化的影响。
与相同背景的野生型小鼠相比，P301L/COMT - 小鼠表现出运动亢进表型和感觉运动门控缺陷，并且相对于具有COMT功能的P301L小鼠，tau磷酸化增加。匹莫范色林使P301L/COMT - 和rTg（P301L）4510小鼠的运动亢进表型正常化，但对两种模型中的感觉运动门控均无影响。匹莫范色林治疗对tau磷酸化模式影响不大。
这些数据表明匹莫范色林可改善tau驱动的过度运动。鉴于AD中诸如踱步等异常运动行为相关的发病率以及缺乏有效治疗方法，未来有必要研究匹莫范色林对该综合征患者活动记录仪的影响。
