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

ABSTRACT

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-ß (Aß) pathology in transgenic AD models have been reported. The conflict is resolved here as likely being due to the different hAßPP transgenes used in the different AD mouse models. CTSB gene KO reduced wild-type (Wt) ß-secretase activity, brain Aß, pyroglutamate-Aß, amyloid plaque, and memory deficits in models that used cDNA transgenes expressing hAßPP isoform 695. But in models that used mutated mini transgenes expressing hAßPP isoforms 751 and 770, CTSB KO had no effect on Wt ß-secretase activity and slightly increased brain Aß. All models expressed the AßPP transgenes in neurons. These conflicting results in Wt ß-secretase activity models can be explained by hAßPP isoform specific cellular expression, proteolysis, and subcellular processing. CTSB KO had no effect on Swedish mutant (Swe) ß-secretase activity in hAßPP695 and hAßPP751/770 models. Different proteolytic sensitivities for hAßPP with Wt versus Swe ß-secretase site sequences may explain the different CTSB ß-secretase effects in hAßPP695 models. But since the vast majority of sporadic AD patients have Wt ß-secretase activity, the CTSB effects on Swe ß-secretase activity are of little importance to the general AD population. As neurons naturally produce and process hAßPP isoform 695 and not the 751 and 770 isoforms, only the hAßPP695 Wt models mimic the natural neuronal hAßPP processing and Aß production occurring in most AD patients. Significantly, these CTSB KO findings in the hAßPP695 Wt models demonstrate that CTSB participates in memory deficits and production of pyroglutamate-Aß (pyroglu-Aß), which provide rationale for future investigation of CTSB inhibitors in AD therapeutics development.