Premium
P3‐050: Overexpression of the kynurenine pathway enzyme tryptophan 2,3‐dioxygenase in triple‐transgenic (3xTg) Alzheimer's disease mouse brain
Author(s) -
Wu Wei,
Nicolazzo Joseph,
Chung Roger,
Cullen Karen,
Ball Helen,
Guillemin Gilles
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1489
Subject(s) - kynurenine , kynurenine pathway , genetically modified mouse , medicine , endocrinology , hippocampus , messenger rna , cerebellum , immunohistochemistry , biology , tryptophan , western blot , transgene , biochemistry , gene , amino acid
more generalized tauopathy caused by increased GSK3b activity, biGT mice survive longer than parental Tau.P301L mice (15-24 months)(Terwel et al, 2008). Conversely, neuron-specific GSK3ß deficiency shortens lifespan of Tau.P301LxGSK3ß(n-/-) to 2-3 months (unpublished). Methods: Body-weight, motor functions, survival, plethysmography of the different genotypes, and effect of O-GlcNAcase inhibitor. Results: Kaplan-Meyer curves on large cohorts demonstrate survival half-life of 9.2 months in Tau.P301L mice (n1⁄480 M/154 F), 15 months in biGT mice (n1⁄454 M/60 F) and 2-3 months in GSK3b (n-/-)x Tau.P301L mice (n1⁄485 M/85 F). No gender differences were evident.Tau.P301L mice evolve from cognitive improved at young age (Boekhoorn et al, 2007) to cognitive defective at 4-6 months, with late motor dysfunction and breathing defects (>7months) correlating with progressive tauopathy in brainstem and spinal cord. biGTmice have improved, nearly normal upper-airway function relative to agematched, dysfunctional Tau.P301L mice. In contrast, young GSK3b (n-/-) xTau.P301L mice suffer severe upper-airway dysfunction and unstable respiratory cycles. Survival and breathing dysfunction correlate snugly in the 3 genotypes expressing same Tau.P301L and differ only in GSK3b activity. Treatment of Tau.P301L with O-GlcNAcase inhibitor increased overall O-GlcNAcylated proteins rapidly (6-24 hours) and significantly improved their breathing parameters (3 days). Chronic treatment of Tau.P301L mice (from age 7 to 9.5 months) significantly mitigated loss in body-weight and motor deficits (clasping, rotarod) and markedly improved survival: w60% of treated mice vs 10% in placebo group. Conclusions: Very close correlation of increased and decreased GSK3b-activity with aggravated and mitigated breathing dysfunction, and shortened and prolonged lifespan in Tau.P301L mice, respectively. Data corroborate that breathing dysfunction causes premature death and identify GSK3b as major controlling factor of tau-induced breathing dysfunction in brainstem (Dutschmann et al, 2010). Inhibition of O-GlcNAcase prolongs survival, rescues or delays motor impairment and mitigates brainstem breathing defects of ageing TauP301L mice.