Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders
Introduction
Neurodegeneration of Alzheimer's disease (AD), traumatic brain injury (TBI), and related dementia (ADRD) disorders displays behavioral deficits in memory, cognition, problem solving, executive function, language, emotion, and related brain functions [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]]. Severe cognitive decline, dementia, occurs in ADRD disorders of Alzheimer's disease [[1], [2], [3]], traumatic brain injury (TBI) [[4], [5], [6]], brain ischemia and stroke [[7], [8], [9]], and related neurodegenerative brain disorders [[10], [11], [12], [13], [14], [15]]. These disorders are widespread affecting more than 47 million people worldwide, with high prevalence in the aged population.
There have been tremendous efforts in the field of drug discovery for AD, TBI, and numerous related ADRD disorders, but decades of drug development research have not yet yielded effective therapeutics to attenuate or reverse these neurodegenerative diseases. Advancements in dementia therapeutics strategies will necessitate elucidation of novel molecular mechanisms in ADRD which can be modulated through drug intervention to ameliorate the behavioral dysfunctions and neuropathology of ADRD disorders. Investigation of novel targets of ADRD will advance opportunities for therapeutics development to extend prior efforts for targeting neuropathological amyloid-β (Aβ) [[16], [17], [18], [19], [20]], phospho-tau [[21], [22], [23]], and related mechanisms [[24], [25], [26], [27]].
Cathepsin B, a lysosomal cysteine protease, represents a candidate drug target for AD, TBI, and related brain disorders. Cathepsin B has been shown by numerous studies to participate in AD and TBI cognitive and behavioral deficits, and in neuropathology. This review highlights the multi-disciplinary research of cathepsin B in human clinical studies, and in AD, TBI, and related animal models using cathepsin B gene knockout and chemical inhibition. Findings from these studies support the hypothesis that lysosomal leakage of cathepsin B to the cytosol leads to neurodegeneration and behavioral deficits in AD, TBI, and related brain disorders. These results provide the rationale for investigation of cathepsin B as a mechanistic drug target for therapeutics discovery and development for AD, TBI, and related dementia.
Section snippets
Cathepsin B elevation in human clinical AD, TBI, and related neurodegenerative disorders
Several studies have shown increased levels of cathepsin B protein or activity in plasma, CSF, and amyloid plaques in human AD, TBI, and related neurodegenerative diseases (Table 1) [[28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39]]. Importantly, increased plasma cathepsin B correlates with cognitive dysfunction in AD [29] and severe trauma outcomes [36].
Human brain gene expression of cathepsin B at young to adult ages
Analyses of cathepsin B expression in human brain illustrates its abundant expression in hippocampal and cortical regions which are responsible for cognitive and behavioral functions [40]. Cathepsin B mRNA expression is illustrated as RNAseq data overlaid on a human brain MRI image (from the Allen human brain atlas, https://human.brain-map.org/) [41,42] in Fig. 2a.
Cathepsin B is one of the most abundant lysosomal cathepsin proteases expressed in human brain compared to the 15 member lysosomal
Cathepsin B participates in behavioral deficits and neuropathology in animal models of AD, TBI, and related brain disorders
Numerous investigations of animal models of AD, TBI, and related dementia disorders demonstrate that cathepsin B is elevated during brain dysfunction and pathogenesis [29,[44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74]]. Furthermore, gene knockout of cathepsin B in these animal models of brain disorders results in amelioration of behavioral deficits and
Maturation of preprocathepsin B, member of the cysteine cathepsin protease family
Cathepsin B is a lysosomal cysteine protease belonging to the clan CA and the papain-like family C1A. The other C1A papain-like cysteine proteases in humans are cathepsins C, F, H, K, L, O, S, V, W, and Z (also known as cathepsin X) [40,43,114]. The cathepsin family also includes the aspartyl proteases cathepsins D and E, and the serine proteases cathepsins A and G. These cathepsins comprise the 15 protease members of lysosomal cathepsin proteases. Cathepsin B is among the most abundantly
Selective CA-074 inhibitor of cathepsin B
Development of inhibitors of cathepsin B may lead to novel therapeutic agents for the treatment of the devastating AD, TBI, and related cognitive and behavioral deficits. Selectivity of inhibitors for cathepsin B compared to other members of the cysteine cathepsin family is important for targeted inhibition of cathepsin B without disturbing other related proteases and associated functions. Distinct structural features of cathepsin B have resulted in design and synthesis of the highly selective
Regulation of cathepsin B proteolysis by its distinct occluding loop
Cathepsin B uniquely possesses the occluding loop compared to other cysteine cathepsins [[132], [133], [134], [135], [136], [137]]. The occluding loop is located near the enzyme's substrate binding pocket containing the active site Cys-29 residue [100,132] (Fig. 5) which catalyzes endopeptidase and dipeptidyl carboxypeptidase activities. Thus, these activities are influenced by the occluding situated near the primed subsites which favor binding of peptide substrates with two residues
Lysosomal leakage of cathepsin B to the cytosol in cell death and inflammation of AD, TBI, and related brain disorders
Abnormal lysosomal leakage of cathepsin B into the cytosol of cells occurs as an integral mechanism for cell death and inflammation in AD, TBI, and related brain disorders. Cathepsin B and cathepsin proteases are normally sequestered within lysosome organelles for homeostasis by degradation of cellular proteins into amino acids [138,139]. In AD, TBI, and related brain disorders, lysosomal membranes lose their integrity to result in lysosomal leakage and redistribution of cathepsin B to the
Translocation of lysosomal cathepsin B to the cytosol in neurodegeneration
Lysosomal leakage results in the pathogenic redistribution of cathepsin B from the lysosome to the cytosol in neurodegeneration, in contrast to the normal intra-lysosomal location of cathepsin B for protein degradation and homeostasis, which leads to the hypothesis that abnormal cytosolic cathepsin B participates in AD and TBI-related dysfunctions (illustrated in Fig. 6). The key question is what are the cytosolic substrates of cathepsin B that lead to neurodegeneration? The profiles of
Conclusions and future perspectives
The hypothesis that lysosomal leakage of pathogenic cathepsin B to the cytosol results in neurodegeneration and behavioral deficits of AD, TBI, and related brain disorders (Fig. 6) is supported by ample evidence from clinical and animal model studies of AD, TBI, and related brain disorders. This leads to the question of what are the cytosolic substrates of cathepsin B that lead to neurodegeneration? Current data implicate cathepsin B substrates involved in cell death and inflammatory pathways.
Declaration of Competing Interest
None
Acknowledgments
This work was supported by NIH grant R01NS109075 to VH, and NIH grant R41NS110147 to GH. The authors thank Michael Gilson and the Center for Drug Discovery Innovation (cDDI) at UC San Diego for advice and resources for the Molecular Operating Environment (MOE) analyses.
V. Hook organized the manuscript for participation by coauthors and wrote the manuscript. MY, CM, and AJO conducted the MOE representation of the cathepsin B structure complexed with the CA-074 inhibitors, and conducted
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