Elevated levels of tripeptidyl peptidase 1 do not ameliorate pathogenesis in a mouse model of Alzheimer disease.

One potential therapeutic strategy for Alzheimer disease (AD) is to promote degradation of amyloid beta (Aβ) and we previously demonstrated that the lysosomal protease tripeptidyl peptidase 1 (TPP1) can degrade Aβ fibrils in vitro. In this study, we tested the hypothesis that increasing levels of TPP1 might promote degradation of Aβ under physiological conditions, slowing or preventing its accumulation in the brain with subsequent therapeutic benefits. We used 2 approaches to increase TPP1 activity in the brain of J20 mice, an AD model that accumulates Aβ and exhibits cognitive defects: transgenic overexpression of TPP1 in the brain and a pharmacological approach employing administration of recombinant TPP1. While we clearly observed the expected AD phenotype of the J20 mice based on pathology and measurement of behavioral and cognitive defects, we found that elevation of TPP1 activity by either experimental approach failed to have any measurable beneficial effect on disease phenotype.