背景:淀粉样蛋白β(Aβ)损害神经活动(功能性充血)引起的脑血流量(CBF)增加。组织型纤溶酶原激活剂(tPA)是功能性充血所必需的,在Aβ积累的小鼠模型中,tPA缺乏会导致神经血管和认知障碍。然而,补充tPA能否挽救Aβ诱导的神经血管和认知功能障碍,目前尚不清楚.
方法:Tg2576小鼠和野生型同窝动物从11至12月龄开始每周5天接受鼻内tPA(0.8mg/kg/天)或载体,并在3个月后进行评估。
结果:用tPA治疗Tg2576小鼠恢复了静息CBF,防止功能性充血的衰减,并改善了嵌套行为。这些作用与减少脑萎缩和脑淀粉样血管病有关,但不是实质淀粉样蛋白.
结论:这些发现强调了tPA缺乏在与淀粉样蛋白病理相关的神经血管和认知功能障碍中的关键作用,并提出涉及tPA重建的潜在治疗策略。
结论:淀粉样β(Aβ)诱导神经血管功能障碍,并损害神经活动引起的脑血流量增加(功能性充血)。组织型纤溶酶原激活物(tPA)缺乏导致Aβ引起的神经血管和认知功能障碍。在具有花状淀粉样蛋白病理学的小鼠中,鼻内施用tPA可挽救神经血管和认知功能障碍,并减少脑萎缩和脑淀粉样血管病。tPA缺乏在Aβ诱导的神经血管和认知功能障碍中起着至关重要的作用,tPA重建可能具有治疗价值。
Amyloid beta (Aβ) impairs the cerebral blood flow (CBF) increase induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) is required for functional hyperemia, and in mouse models of Aβ accumulation tPA deficiency contributes to neurovascular and cognitive impairment. However, it remains unknown if tPA supplementation can rescue Aβ-induced neurovascular and cognitive dysfunction.
Tg2576 mice and wild-type littermates received intranasal tPA (0.8 mg/kg/day) or vehicle 5 days a week starting at 11 to 12 months of age and were assessed 3 months later.
Treatment of Tg2576 mice with tPA restored resting CBF, prevented the attenuation in functional hyperemia, and improved nesting behavior. These effects were associated with reduced cerebral atrophy and cerebral amyloid angiopathy, but not parenchymal amyloid.
These findings highlight the key role of tPA deficiency in the neurovascular and cognitive dysfunction associated with amyloid pathology, and suggest potential therapeutic strategies involving tPA reconstitution.
Amyloid beta (Aβ) induces neurovascular dysfunction and impairs the increase of cerebral blood flow induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) deficiency contributes to the neurovascular and cognitive dysfunction caused by Aβ. In mice with florid amyloid pathology intranasal administration of tPA rescues the neurovascular and cognitive dysfunction and reduces brain atrophy and cerebral amyloid angiopathy. tPA deficiency plays a crucial role in neurovascular and cognitive dysfunction induced by Aβ and tPA reconstitution may be of therapeutic value.