Cathepsin B Deficiency Improves Memory Deficits and Reduces Amyloid-β in hAβPP Mouse Models Representing the Major Sporadic Alzheimer's Disease Condition.
Cathepsin B Deficiency Improves Memory Deficits and Reduces Amyloid-β in hAβPP Mouse Models Representing the Major Sporadic Alzheimer's Disease Condition.
复制标题
DOI：
10.3233/jad-221005
复制
发表时间：
2023
影响因子：
4
通讯作者：
Hook, Vivian
中科院分区：
文献类型：
--
作者：
Hook, Gregory;Kindy, Mark;Hook, Vivian
关键词：
溶酶体半胱氨酸蛋白酶组织蛋白酶B(CTSB)被认为是阿尔茨海默病(AD)的生物标志物，因为AD患者血清CTSB升高与认知功能障碍有关。此外，在非转基因和转基因AD动物模型中的CTSB基因敲除(KO)表明，消除CTSB可以改善记忆缺陷。然而，在转基因AD模型中，关于淀粉样蛋白β(Aβ)病理的CTSB KO结果相互矛盾。冲突在这里被解决，因为可能是由于在不同的AD小鼠模型中使用了不同的HAβPP转基因。CTSB基因KO降低了野生型(Wt)β分泌酶活性、脑淀粉样蛋白(Aβ，Aβ)、焦谷氨酸Aβ、淀粉样斑块，以及使用表达hAβPP亚型695的c DNA转基因模型的记忆缺陷。但在使用表达HAβPP亚型751和770的微小转基因突变的模型中，CTSBKO对Wtβ-分泌酶活性没有影响，并略微增加了脑Aβ。所有模型都在神经元中表达了转基因。Wtβ-分泌酶活性模型中的这些相互矛盾的结果可以用HAβPP亚型特异性的细胞表达、蛋白分解和亚细胞加工来解释。在HAβPP695和HAβPP751/770模型中，CTSB KO对瑞典突变体(SWE)β分泌酶活性没有影响。具有Wt和Sweβ分泌酶序列的HAβPP对蛋白质的不同敏感性可能解释了在HAβPP695模型中不同的βCTSB分泌酶效应。但由于绝大多数散发性AD患者具有Wtβ-分泌酶活性，因此CTSB对SWE-β-分泌酶活性的影响对普通AD人群来说并不重要。由于神经元自然产生和处理HAβPP亚型695，而不是751WT和770亚型，因此只有HAβPP695Wt模型模拟了大多数AD患者中自然产生的神经元HAβPP处理和Aβ产生。值得注意的是，在HAβPP695Wt模型中的这些CTSB KO发现表明CTSB参与了记忆缺陷和焦谷氨酸-Aβ(焦谷氨酸-Aβ)的产生，这为未来CTSB抑制剂在AD治疗开发中的研究提供了理论基础。
The lysosomal cysteine protease cathepsin B (CTSB) has been suggested as a biomarker for Alzheimer’s disease (AD) because elevated serum CTSB in AD patients correlated with cognitive dysfunction. Furthermore, CTSB gene knockout (KO) in non-transgenic and transgenic AD animal models showed that elimination of CTSB improved memory deficits. However, conflicting CTSB KO results on amyloid-β (Aβ) pathology in transgenic AD models have been reported. The conflict is resolved here as likely being due to the different hAβPP transgenes used in the different AD mouse models. CTSB gene KO reduced wild-type (Wt) β-secretase activity, brain amyloid-β (Aβ), pyroglutamate-Aβ, amyloid plaque, and memory deficits in models with using cDNA transgenes expressing hAβPP isoform 695. But in models using mutated mini transgenes expressing hAβPP isoforms 751 and 770, CTSB KO had no effect on Wt β-secretase activity and slightly increased brain Aβ. All models expressed the transgene in neurons. These conflicting results in Wt β-secretase activity models can be explained by hAβPP isoform specific cellular expression, proteolysis and subcellular processing. CTSB KO had no effect on Swedish mutant (Swe) β-secretase activity in hAβPP695 and hAβPP751/770 models. Different proteolytic sensitivities for hAβPP with Wt vs. Swe β-secretase site sequences may explain the different CTSB β-secretase effects in hAβPP695 models. But since the vast majority of sporadic AD patients have Wt β-secretase activity, the CTSB effects on Swe β-secretase activity are of little importance to the general AD population. As neurons naturally produce and process hAβPP isoform 695 and not the 751 and 770 isoforms, only the hAβPP695 Wt models mimic the natural neuronal hAβPP processing and Aβ production occurring in most AD patients. Significantly, these CTSB KO findings in the hAβPP695 Wt models demonstrate CTSB participation in memory deficits and production of pyroglutamate-Aβ (pyroglu-Aβ), which provide rationale for future investigation of CTSB inhibitors in AD therapeutics development.
DOI：
10.1159/000358430
发表时间：
2014
期刊：
Neuro-degenerative diseases
影响因子：
--
作者：
Cynis H;Funkelstein L;Toneff T;Mosier C;Ziegler M;Koch B;Demuth HU;Hook V
通讯作者：
Hook V