Cataldo Anne M, Peterhoff Corrinne M, Schmidt Stephen D, Terio Nicole B, Duff Karen, Beard Margaret, Mathews Paul M, Nixon Ralph A
Laboratory for Molecular Neuropathology, Mailman Research Center, McLean Hospital, Belmont, Massachusetts, USA.
J Neuropathol Exp Neurol. 2004 Aug;63(8):821-30. doi: 10.1093/jnen/63.8.821.
The neuronal lysosomal system is a major degradative pathway, induced by cell stress and closely linked to Alzheimer disease (AD) and other neurodegenerative diseases. Here, we show that mutations of presenilin (PS) 1 and 2, which cause familial early-onset AD (FAD), induce more severe lysosomal system neuropathology in humans than does sporadic AD (SAD). Cathepsin D and B levels were higher in PS-FAD neocortex than in SAD and, unlike neurons in SAD, expressed higher levels of the cation-independent mannose-6-phosphate receptor. Lysosomal pathology was also evident in more populations of neurons in PS-FAD brains, including the less vulnerable neurons in laminae II and IV and affected neurons contained high numbers of hydrolase-positive vesicular compartments with a broader range of abnormal morphology. In transgenic mice expressing mutant amyloid precursor protein (APPswe), introducing mutant PSI significantly upregulated the lysosomal system in neocortical and hippocampal neurons. This upregulation, though milder in severity, resembled that seen in human PS-FAD. Accumulation of hydrolases in dystrophic neurites in senile plaques was particularly strong, suggesting that amyloid deposition may be a stimulus for local mobilization of the lysosomal system. PS1 mice lacking the APPswe transgene also had a mild lysosomal response in some neuronal populations, which was not seen in the APPswe mice. Our findings suggest that presenilin mutations have amyloid-independent effects on the lysosomal system, which are synergistic with the lysosomal system pathology that is associated with beta-amyloid.
神经元溶酶体系统是一种主要的降解途径，由细胞应激诱导，与阿尔茨海默病（AD）及其他神经退行性疾病密切相关。在此，我们表明，导致家族性早发性AD（FAD）的早老素（PS）1和2突变，在人类中诱导的溶酶体系统神经病理学比散发性AD（SAD）更严重。PS-FAD新皮质中的组织蛋白酶D和B水平高于SAD，并且与SAD中的神经元不同，其表达的非依赖阳离子的甘露糖-6-磷酸受体水平更高。溶酶体病理学在PS-FAD脑的更多神经元群体中也很明显，包括第II和IV层中较不易受损的神经元，并且受影响的神经元含有大量水解酶阳性的囊泡区室，其形态异常范围更广。在表达突变淀粉样前体蛋白（APPswe）的转基因小鼠中，引入突变的PS1显著上调了新皮质和海马神经元中的溶酶体系统。这种上调虽然严重程度较轻，但类似于在人类PS-FAD中所见。老年斑中营养不良性神经突中水解酶的积累尤为强烈，这表明淀粉样蛋白沉积可能是溶酶体系统局部动员的刺激因素。缺乏APPswe转基因的PS1小鼠在一些神经元群体中也有轻微的溶酶体反应，而在APPswe小鼠中未观察到这种反应。我们的研究结果表明，早老素突变对溶酶体系统具有不依赖淀粉样蛋白的作用，这与与β-淀粉样蛋白相关的溶酶体系统病理学具有协同作用。
