Puromycin-sensitive aminopeptidase (PSA/NPEPPS) impedes development of neuropathology in HPSA/TAUP301L double-transgenic mice

Academic Article

Abstract

  • Accumulation of neurotoxic hyperphosphorylated TAU protein is a major pathological hallmark of Alzheimer disease and other neurodegenerative dementias collectively called tauopathies. Puromycin-sensitive amino- peptidase (PSA/NPEPPS) is a novel modifier of TAU-induced neurodegeneration with neuroprotective effects via direct proteolysis of TAU protein. Here, to examine the effects of PSA/NPEPPS overexpression in vivo in the mammalian system, we generated and crossed BAC-PSA/NPEPPS transgenic mice with the TAUP301L mouse model of neurodegeneration. PSA/NPEPPS activity in the brain and peripheral tissues of human PSA/NPEPPS (hPSA) mice was elevated by ~2-3-fold with no noticeable deleterious physiological effects. Double-transgenic animals for hPSA and TAUP301L transgenes demonstrated a distinct trend for delayed paralysis and showed significantly improved motor neuron counts, no gliosis and markedly reduced levels of total and hyperphosphorylated TAU in the spinal cord, brain stem, cortex, hippocampus and cerebellum of adult and aged animals when compared with TAUP301L mice. Furthermore, endogenous TAU protein abun- dance in human neuroblastoma SH-SY5Y cells was significantly reduced or augmented by overexpression or knockdown of PSA/NPEPPS, respectively. This study demonstrated that without showing neurotoxic effects, elevation of PSA/NPEPPS activity in vivo effectively blocks accumulation of soluble hyperphosphorylated TAU protein and slows down the disease progression in the mammalian system. Our data suggest that increasing PSA/NPEPPS activity may be a feasible therapeutic approach to eliminate accumulation of unwanted toxic substrates such as TAU. © The Author 2011. Published by Oxford University Press. All rights reserved.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Kudo LC; Parfenova L; Ren G; Vi N; Hui M; Ma Z; Lau K; Gray M; Bardag-Gorce F; Wiedau-Pazos M
  • Start Page

  • 1820
  • End Page

  • 1833
  • Volume

  • 20
  • Issue

  • 9