Lysosomal Enzyme Tripeptidyl Peptidase 1 Plays a Role in Degradation of Beta Amyloid Fibrils

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid plaques surrounded by microglia. In cell culture, microglia internalize fibrillar β-amyloid but do not degrade it efficiently. Unactivated microglia have a relatively high lysosomal pH, which impairs the activity of lysosomal proteases. Previous studies showed that activation of microglia with macrophage colony stimulating factor decreases lysosomal pH and enhances fibrillar β-amyloid degradation. We investigated the role of the lysosomal protease tripeptidyl peptidase 1 (TPP1) in cell culture and in a mouse model of Alzheimer’s disease. Increased levels of TPP1 in unactivated microglia enhanced fibrillar β-amyloid degradation. Conversely, reduction of TPP1 led to decreased fibrillar β-amyloid degradation in activated microglia, macrophages, and other cells that degrade fibrillar β-amyloid efficiently. Reduction of TPP1 in an AD model mouse using a gene-targeted hypomorphic Tpp1 allele increased plaque burden. These results suggest that decreased TPP1 potentiates AD pathogenesis and that strategies to increase TPP1 activity may have therapeutic value. Highlights In microglia, TPP1 is important for the degradation of fibrillar β-amyloid. Increased TPP1 in microglia results in enhanced fibrillar β-amyloid degradation. In an AD mouse model, reduction of TPP1 led to increased amyloid plaque deposition.