Deletion of the Cathepsin B Gene Improves Memory Deficits in a Transgenic Alzheimer's Disease Mouse Model Expressing AβPP Containing the Wild-Type β-Secretase Site Sequence

Abstract

Therapeutic agents that improve the memory loss of Alzheimer’s disease (AD) may eventually be developed if drug targets are identified that improve memory deficits in appropriate AD animal models. One such target is β-secretase which, in most AD patients, cleaves the wild-type (WT) β-secretase site sequence of the amyloid-β protein precursor (AβPP) to produce neurotoxic amyloid-β (Aβ). Thus, an animal model representing most AD patients for evaluating β-secretase effects on memory deficits is one that expresses human AβPP containing the WT β-secretase site sequence. BACE1 and cathepsin B (CatB) proteases have β-secretase activity, but gene knockout studies have not yet validated that the absence of these proteases improves memory deficits in such an animal model. This study assessed the effects of deleting these protease genes on memory deficits in the AD mouse model expressing human AβPP containing the WT β-secretase site sequence and the London γ-secretase site (AβPPWT/Lon mice). Knockout of the CatB gene in the AβPPWT/Lon mice improved memory deficits and altered the pattern of Aβ-related biomarkers in a manner consistent with CatB having WT β-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the AβPPWT/Lon mice. These data are the first to show that knockout of a putative β-secretase gene results in improved memory in an AD animal model expressing the WT β-secretase site sequence of AβPP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients.

Brain Pyroglutamate Amyloid-β is Produced by Cathepsin B and is Reduced by the Cysteine Protease Inhibitor E64d, Representing a Potential Alzheimer's Disease Therapeutic

“…Thus, in order to evaluate the β-secretase production of pGlu-Aβ occurring in the brain neurons of most AD patients, it is critical that the transgenic model express AβPP containing the wt β-secretase site sequence and isoform AβPP-695. Two models having these features are those expressing human wt AβPP (AβPPwt), which is that found in most AD patients [49], and human AβPP-695 containing the London mutation (AβPPLon), which has the wt β-secretase site and a rare familial mutation near the AβPP C-terminal cleavage site of Aβ [50]. AβPPwt and AβPPLon mice overproduce brain flAβ(1-40/42) and develop memory deficits, but AβPPLon mice are also known to produce pGlu-Aβ(3-42) and develop brain Aβ plaque pathology and inflammatory processes, which mimic that seen in AD patients [51, 52].…”

The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

“…68,69 Our previous work in transgenic AD mice showed that deleting the cathepsin B gene or treating them with E64d (oral administration) causes major reductions in brain Ab, brain amyloid plaque, and improves memory deficits. 15,17,70,71 Thus, treating TBI patients with a cathepsin B inhibitor may also reduce the subsequent long-term risk of AD.…”

Differential role of calpain-dependent protein cleavage in intermediate and long-term operant memory in Aplysia

“…Cathepsins are lysosomal proteases whose activity has been associated with inflammation, autophagy, apopotosis and neurodegeneration (Stoka et al, 2016) and for which inhibition has been suggested as therapeutic to enhance memory (Hook et al, 2011; Kindy et al, 2012). In general, cathepsin activity appears to be associated with decrements in learning and memory.…”