title: Puromycin-sensitive aminopeptidase (PSA/NPEPPS) impedes development of neuropathology in hPSA/TAU(P301L) double-transgenic mice.
abstract: Accumulation of neurotoxic hyperphosphorylated TAU protein is a major pathological hallmark of Alzheimer disease and other neurodegenerative dementias collectively called tauopathies. Puromycin-sensitive aminopeptidase (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 TAU(P301L) 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 TAU(P301L) 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 TAU(P301L) mice. Furthermore, endogenous TAU protein abundance 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.
authors.affiliation: NeuroInDx Inc., 1655 East 28th Street, Signal Hill, CA 90755, USA.
authors.forename: Lili C
authors.initials: LC
authors.lastname: Kudo
authors.forename: Liubov
authors.initials: L
authors.lastname: Parfenova
authors.forename: Guijie
authors.initials: G
authors.lastname: Ren
authors.forename: Nancy
authors.initials: N
authors.lastname: Vi
authors.forename: Maria
authors.initials: M
authors.lastname: Hui
authors.forename: Zhongcai
authors.initials: Z
authors.lastname: Ma
authors.forename: Kimbley
authors.initials: K
authors.lastname: Lau
authors.forename: Michelle
authors.initials: M
authors.lastname: Gray
authors.forename: Fawzia
authors.initials: F
authors.lastname: Bardag-Gorce
authors.forename: Martina
authors.initials: M
authors.lastname: Wiedau-Pazos
authors.forename: Koon-Sea
authors.initials: KS
authors.lastname: Hui
authors.forename: Stanislav L
authors.initials: SL
authors.lastname: Karsten
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D008666:Metalloendopeptidases; C117631:NPEPPS protein, human