Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Curr Alzheimer Res. 2022;19(4):317-329. doi: 10.2174/1567205019666220509143823.
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.
阿尔茨海默病（AD）是由脑实质中淀粉样β（Aβ）蛋白的异常积累引发的。淀粉样斑块周围的微环境的特征是与溶酶体功能障碍、微管破坏和轴突运输受损相关的突触前末梢（萎缩神经突）肿胀。Aβ诱导的质膜损伤和钙内流可能是形成萎缩神经突的潜在机制。
我们测试了通过脑内给予安全的美国食品和药物管理局批准的表面活性剂泊洛沙姆 188（P188）来促进膜完整性，是否可以减轻体内 AD 病理学。
用迷你渗透泵将几种浓度的 P188 脑内给药给 3 月龄的 5XFAD 雄性小鼠，持续 42 天。42 天后，处死小鼠，评估大脑中的淀粉样蛋白病理、萎缩神经突、致病性小胶质细胞激活、tau 磷酸化和溶酶体/囊泡运输标志物。
P188 在最高浓度 10mM 时是致命的。较低浓度的 P188（1.2、12 和 120μM）耐受性良好。P188 通过激活 γ-分泌酶途径增加脑 Aβ 负荷。P188 处理的小鼠中，萎缩神经突病理加重，表现为 Aβ 沉积周围 LAMP1 积累增加。P188 增加了致病性小胶质细胞的激活。P188 降低了总 tau 水平。溶酶体酶组织蛋白酶 D 和钙依赖性囊泡转运调节剂突触结合蛋白 7（SYT7）在 P188 给药后失调。
P188 脑内给药在 5XFAD 小鼠中加重了淀粉样蛋白病理、萎缩神经突和致病性小胶质细胞的激活。这些影响与溶酶体功能障碍和质膜囊泡运输失调相关。P188 不是针对 AD 发病机制的有前途的治疗策略。
