Cathepsin B (CTSB) is a powerful lysosomal
protease. This review evaluated CTSB gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion of the CTSB gene resulted in significant improvements in behavioral deficits, neuropathology, and/or
biomarkers in
traumatic brain injury,
ischemia, inflammatory
pain,
opiate tolerance,
epilepsy, aging, transgenic
Alzheimer's disease (AD), and
periodontitis AD models as shown in 12 studies. One study found beneficial effects for double CTSB and
cathepsin S KO mice in a
multiple sclerosis model. Transgenic AD models using
amyloid precursor
protein (APP) mimicking common sporadic AD in three studies showed that CTSB KO improved memory, neuropathology, and
biomarkers; two studies used APP representing rare familial AD and found no CTSB KO effect, and two studies used highly engineered APP constructs and reported slight increases in a
biomarker. In clinical studies, all reports found that CTSB
enzyme was upregulated in diverse
neurologic disorders, including AD in which elevated CTSB was positively correlated with
cognitive dysfunction. In a wide range of neurologic animal models, CTSB was also upregulated and not downregulated. Further, human genetic mutation data provided precedence for CTSB upregulation causing disease. Thus, the consilience of data is that CTSB gene KO results in improved brain dysfunction and reduced pathology through blockade of CTSB
enzyme upregulation that causes human neurologic disease phenotypes. The overall findings provide strong support for CTSB as a rational
drug target and for CTSB inhibitors as therapeutic candidates for a wide range of
neurologic disorders. SIGNIFICANCE STATEMENT: This review provides a comprehensive compilation of the extensive data on the effects of deleting the
cathepsin B (CTSB) gene in neurological and aging mouse models of
brain disorders. Mice lacking the CTSB gene display improved neurobehavioral deficits, reduced neuropathology, and amelioration of neuronal cell death and inflammatory
biomarkers. The significance of the compelling CTSB evidence is that the data consilience validates CTSB as a
drug target for discovery of CTSB inhibitors as potential
therapeutics for treating numerous neurological diseases.