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Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders.

ABSTRACT: Investigations of Alzheimer's disease (AD), traumatic brain injury (TBI), and related brain disorders have provided extensive evidence for involvement of cathepsin B, a lysosomal cysteine protease, in mediating the behavioral deficits and neuropathology of these neurodegenerative diseases. This review integrates findings of cathepsin B regulation in clinical biomarker studies, animal model genetic and inhibitor evaluations, structural studies, and lysosomal cell biological mechanisms in AD, TBI, and related brain disorders. The results together indicate the role of cathepsin B in the behavioral deficits and neuropathology of these disorders. Lysosomal leakage occurs in AD and TBI, and related neurodegeneration, which leads to the hypothesis that cathepsin B is redistributed from the lysosome to the cytosol where it initiates cell death and inflammation processes associated with neurodegeneration. These results together implicate cathepsin B as a major contributor to these neuropathological changes and behavioral deficits. These findings support the investigation of cathepsin B as a potential drug target for therapeutic discovery and treatment of AD, TBI, and TBI-related brain disorders.

SUBMITTER: Hook V

PROVIDER: S-EPMC7261628 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders.

Hook Vivian V Yoon Michael M Mosier Charles C Ito Gen G Podvin Sonia S Head Brian P BP Rissman Robert R O'Donoghue Anthony J AJ Hook Gregory G

Biochimica et biophysica acta. Proteins and proteomics 20200417 8

Investigations of Alzheimer's disease (AD), traumatic brain injury (TBI), and related brain disorders have provided extensive evidence for involvement of cathepsin B, a lysosomal cysteine protease, in mediating the behavioral deficits and neuropathology of these neurodegenerative diseases. This review integrates findings of cathepsin B regulation in clinical biomarker studies, animal model genetic and inhibitor evaluations, structural studies, and lysosomal cell biological mechanisms in AD, TBI, ...[more]

PMID: 32305689

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Project description:ObjectiveTraumatic brain injury (TBI) is a heterogeneous disease with multiple neurological deficits that evolve over time. It is also associated with an increased incidence of neurodegenerative diseases. Accordingly, clinicians need better tools to predict a patient's long-term prognosis.MethodsDiffusion-weighted and anatomical MRI data were collected from 17 adolescents (mean age = 15y8mo) with moderate-to-severe TBI and 19 healthy controls. Using a network diffusion model (NDM), we examined the effect of progressive deafferentation and gray matter thinning in young TBI patients. Moreover, using a novel automated inference method, we identified several injury epicenters in order to determine the neural degenerative patterns in each TBI patient.ResultsWe were able to identify the subject-specific patterns of degeneration in each patient. In particular, the hippocampus, temporal cortices, and striatum were frequently found to be the epicenters of degeneration across the TBI patients. Orthogonal transformation of the predicted degeneration, using principal component analysis, identified distinct spatial components in the temporal-hippocampal network and the cortico-striatal network, confirming the vulnerability of these networks to injury. The NDM model, best predictive of the degeneration, was significantly correlated with time since injury, indicating that NDM can potentially capture the pathological progression in the chronic phase of TBI.InterpretationThese findings suggest that network spread may help explain patterns of distant gray matter thinning, which would be consistent with Wallerian degeneration of the white matter connections (i.e., "diaschisis") from diffuse axonal injuries and multifocal contusive injuries, and the neurodegenerative patterns of abnormal protein aggregation and transmission, which are hallmarks of brain changes in TBI. NDM approaches could provide highly subject-specific biomarkers relevant for disease monitoring and personalized therapies in TBI.

Project description:Traumatic brain injury (TBI) increases Ca2+ influx into neurons and desynchronizes mitochondrial function leading to energy depletion and apoptosis. This process may be influenced by brain testosterone (TS) levels, which are known to decrease after TBI. We hypothesized that a TS-based therapy could preserve mitochondrial neuroenergetics after TBI, thereby reducing neurodegeneration. C57BL/6J mice were submitted to sham treatment or severe parasagittal controlled cortical impact (CCI) and were subcutaneously injected with either vehicle (VEH-SHAM and VEH-CCI) or testosterone cypionate (15 mg/kg, TS-CCI) for 10 days. Cortical tissue homogenates ipsilateral to injury were used for neurochemical analysis. The VEH-CCI group displayed an increased Ca2+-induced mitochondrial swelling after the addition of metabolic substrates (pyruvate, malate, glutamate, succinate, and adenosine diphosphate [PMGSA]). The addition of Na+ stimulated mitochondrial Ca2+ extrusion through Na+/Ca2+/Li+ exchanger (NCLX) in VEH-SHAM and TS-CCI, but not in the VEH-CCI group. Reduction in Ca2+ efflux post-injury was associated with impaired mitochondrial membrane potential formation/dissipation, and decreased mitochondrial adenosine triphosphate (ATP)-synthase coupling efficiency. Corroborating evidence of mitochondrial uncoupling was observed with an increase in H2O2 production post-injury, but not in superoxide dismutase (SOD2) protein levels. TS administration significantly reduced these neuroenergetic alterations. At molecular level, TS prevented the increase in pTauSer396 and alpha-Spectrin fragmentation by the Ca2+dependent calpain-2 activation, and decreased both caspase-3 activation and Bax/BCL-2 ratio, which suggests a downregulation of mitochondrial apoptotic signals. Search Tool for the Retrieval of Interacting Genes/Proteins database provided two distinct gene/protein clusters, "upregulated and downregulated," interconnected through SOD2. Therefore, TS administration after a severe CCI improves the mitochondrial Ca2+extrusion through NCLX exchanger and ATP synthesis efficiency, ultimately downregulating the overexpression of molecular drivers of neurodegeneration.

Dataset Information

Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders.

Publications

Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders.

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