阿尔茨海默病(AD)是由淀粉样β(Aβ)蛋白在脑实质中的异常积累引起的。淀粉样蛋白斑块周围的微环境的特征是与溶酶体功能障碍相关的突触前末端(营养不良性神经突)的肿胀,微管破裂,轴突运输受损。Aβ诱导的质膜损伤和钙内流可能是营养不良性神经突形成的潜在机制。
我们测试了通过脑施用安全的FDA批准的表面活性剂分子泊洛沙姆-188(P188)来促进膜完整性是否可以在体内减弱AD病理。
三个月龄的5XFAD雄性小鼠用微型渗透泵在脑中施用几种浓度的P18842天。42天后,对小鼠实施安乐死并评估淀粉样蛋白病理学,营养不良性神经突,致病性小胶质细胞激活,tau磷酸化,和大脑中的溶酶体/囊泡运输标记。
P188在10mM的最高浓度下是致死的。较低浓度的P188(1.2、12和120μM)具有良好的耐受性。P188增加脑Aβ负荷,可能通过激活γ-分泌酶途径。如Aβ沉积物周围的LAMP1积累增加所示,在P188处理的小鼠中,营养不良性神经突病理学加剧。P188增加了致病性小胶质细胞活化。总tau水平降低了P188。溶酶体酶组织蛋白酶D和钙依赖性囊泡运输调节子突触蛋白-7(SYT7)在P188施用后失调。
P188脑递送加剧了淀粉样蛋白病理学,营养不良性神经突,5XFAD小鼠的致病性小胶质细胞活化。这些作用与溶酶体功能障碍和质膜囊泡运输的失调有关。P188不是针对AD发病机理的有希望的治疗策略。
Alzheimer\'s disease (AD) is initiated by aberrant accumulation of amyloid beta (Aβ) protein in the brain parenchyma. The microenvironment surrounding amyloid plaques is characterized by the swelling of presynaptic terminals (dystrophic neurites) associated with lysosomal dysfunction, microtubule disruption, and impaired axonal transport. Aβ-induced plasma membrane damage and calcium influx could be potential mechanisms underlying dystrophic neurite formation.
We tested whether promoting membrane integrity by brain administration of a safe FDA approved surfactant molecule poloxamer-188 (P188) could attenuate AD pathology in vivo.
Three-month-old 5XFAD male mice were administered several concentrations of P188 in the brain for 42 days with mini-osmotic pumps. After 42 days, mice were euthanized and assessed for amyloid pathology, dystrophic neurites, pathogenic microglia activation, tau phosphorylation, and lysosomal / vesicular trafficking markers in the brain.
P188 was lethal at the highest concentration of 10mM. Lower concentrations of P188 (1.2, 12, and 120μM) were well tolerated. P188 increased brain Aβ burden, potentially through activation of the γ-secretase pathway. Dystrophic neurite pathology was exacerbated in P188 treated mice as indicated by increased LAMP1 accumulation around Aβ deposits. Pathogenic microglial activation was increased by P188. Total tau levels were decreased by P188. Lysosomal enzyme cathepsin D and calciumdependent vesicular trafficking regulator synaptotagmin-7 (SYT7) were dysregulated upon P188 administration.
P188 brain delivery exacerbated amyloid pathology, dystrophic neurites, and pathogenic microglial activation in 5XFAD mice. These effects correlated with lysosomal dysfunction and dysregulation of plasma membrane vesicular trafficking. P188 is not a promising therapeutic strategy against AD pathogenesis.