MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, Massachusetts.
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, Massachusetts
eNeuro. 2024 Jan 10;11(1). doi: 10.1523/ENEURO.0258-23.2023. Print 2024 Jan.
Genome wide association study (GWAS) uncovered Alzheimer's disease (AD) risk genes linked to the endo-lysosomal pathway. This pathway seems to be the gateway of protein aggregates, such as tau and α-synuclein, to the cytoplasm. Furthermore, we and others reported that the amyloid precursor protein (APP) C99 is predominantly processed by γ-secretase in the endo-lysosomal compartments, and β-amyloid (Aβ) peptides are enriched in the same subcellular loci. While the role(s) of APP/Aβ in the endo-lysosomal pathway has not been fully established, a recent study reported that Aβ, in particular Aβ42, inhibits cathepsin D (CTSD) activity. Here, we show using a cell-free in vitro assay that Aβ42 also blocks cathepsin B (CTSB) activity. Furthermore, we uncovered that the autocatalytic processing (i.e., conversion of single chain to heavy/light chains) of CTSB and CTSD is accelerated in APP-deficient cells compared with wild-type controls. Taken together, our findings further support the negative regulation of cathepsins by Aβ.
全基因组关联研究（GWAS）揭示了与内体溶酶体途径相关的阿尔茨海默病（AD）风险基因。这条途径似乎是蛋白质聚集体（如 tau 和 α-突触核蛋白）进入细胞质的门户。此外，我们和其他人报道称，淀粉样前体蛋白（APP）C99主要在内体溶酶体区室中被γ-分泌酶处理，β-淀粉样肽（Aβ）在相同的亚细胞位置富集。虽然 APP/Aβ 在内体溶酶体途径中的作用尚未完全确定，但最近的一项研究报道称，Aβ，特别是 Aβ42，抑制组织蛋白酶 D（CTSD）的活性。在这里，我们使用无细胞体外测定表明 Aβ42 也会阻止组织蛋白酶 B（CTSB）的活性。此外，我们发现与野生型对照相比，APP 缺陷细胞中 CTSB 和 CTSD 的自身催化加工（即单链转化为重链/轻链）加速。总之，我们的研究结果进一步支持了 Aβ 对组织蛋白酶的负调控。
