Cathepsin B Deficiency Improves Memory Deficits and Reduces Amyloid-β in hAβPP Mouse Models Representing the Major Sporadic Alzheimer's Disease Condition

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 has been found to correlate 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-beta (A beta) pathology in transgenic AD models have been reported. The conflict is resolved here as likely being due to the different hA beta PP transgenes used in the different AD mouse models. CTSB gene KO reduced wild-type (Wt) beta-secretase activity, brain A beta, pyroglutamate-A beta, amyloid plaque, and memory deficits in models that used cDNA transgenes expressing hA beta PP isoform 695. But in models that used mutated mini transgenes expressing hA beta PP isoforms 751 and 770, CTSB KO had no effect on Wt beta-secretase activity and slightly increased brainA beta. All models expressed the A beta PP transgenes in neurons. These conflicting results in Wt beta-secretase activity models can be explained by hA beta PP isoform specific cellular expression, proteolysis, and subcellular processing. CTSB KO had no effect on Swedish mutant (Swe) beta-secretase activity in hA beta PP695 and hA beta PP751/770 models. Different proteolytic sensitivities for hA beta PP with Wt versus Swe beta-secretase site sequences may explain the different CTSB beta-secretase effects in hA beta PP695 models. But since the vast majority of sporadic AD patients have Wt beta-secretase activity, the CTSB effects on Swe beta-secretase activity are of little importance to the general AD population. As neurons naturally produce and process hA beta PP isoform 695 and not the 751 and 770 isoforms, only the hA beta PP695 Wt models mimic the natural neuronal hA beta PP processing and A beta production occurring in most AD patients. Significantly, these CTSB KO findings in the hA beta PP695 Wt models demonstrate that CTSB participates in memory deficits and production of pyroglutamate-A beta (pyroglu-A beta), which provide rationale for future investigation of CTSB inhibitors in AD therapeutics development.