Feinstein

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Feinstein

  1. 1. Focus on the Locus:LC damage and NAergic treatment in TgAPP mice Douglas L Feinstein Dept of Anesthesiology University of Illinois, Chicago Jesse Brown VA Medical Center December 16th, 2010
  2. 2. In the CNS, reductions of NA can cause: Increased inflammatory responses Increased amyloid burdenReduced levels of neurotrophic factors (NGF, BDNF) Reduced BBB integrity Reduced neural progenitor cell maturation
  3. 3. In rodents, LC lession:Reduces CNS NAIncreases inflammation, neuronal damageDisrupts BBBReduces phagocytosis of amyloidIncreases amyloid burden, cognitive deficits
  4. 4. Evidence for LC damage in TgAPP mice1. Atrophy of TH+ neurons occurs in aged V717F mice German et al. 20052. Loss of TH+ neurons in aged PS:APP mice O’Neil et al. 20073. Hippocampal and cortical NA levels are reduced in PS:APP mice Pugh et al. 20074. NA transporter (NET-1) levels are reduced in PS:APP mice Jardanhazi-Kurutz et al. 2010
  5. 5. Hypothesis: Increasing CNS NA levels will provide benefit in TgAPP mice with endogenous LC damage5xFAD mice (R. Vassar): 3 mutations in hAPP; 2 mutations in PS1 Rapid Aβ accumulation and plaque appearance (6-8 weeks) Neuronal damage; glial inflammation Intraneuronal aggregated Aβ1-42 Cognitive deficits by 5-6 months
  6. 6. LC damage / inflammation in 5xFAD mice A WT LC GFAP+ cells / field 140 * 120 100 TH GFAP 80 60 B 5xFAD 40 20 0 WT 5xFAD TH GFAP
  7. 7. LC inflammation is not associated with plaques A B ThioS GFAP GFAP
  8. 8. LC TH+ cells are stressed in 5xFAD Cell numbers Cell size 140 600 TH cell size (µm2) * TH+ cells / field 120 500 100 400 80 300 60 200 40 20 100 0 0 WT 5xFAD WT 5xFAD
  9. 9. L-DOPS (Droxidopa), a precursor of NA L-DOPS Tyrosine Hydroxylase OH Aromatic amino acid L-AAAD Decarboxylase L-AAADDopamine β-hydroxylase
  10. 10. L-DOPS / Droxidopa Currently in phase III trials for the treatment of Neurogenic Orthostatic HypotensionAlso provides benefit in congenital deficiency of DBH BBB permeableManufactured by Chelsea Therapeutics in the US; Sumitomo in Japan
  11. 11. Treatment protocol4.5 month old male 5xFAD mice (robust Aβ deposition)Treated 3x / week for 4 weeks: L-DOPS 200 mg/kg s.c. Carbidopa 125 mg/kg i.p. Atomoxetine (NA reuptake inhibitor) 20 mg/kg i.p.
  12. 12. Effects in Morris Water Maze Vehicle DOPS Latency to quadreant 60 * 50 40 30 20 10 0 Challenge Challenge Re-challenge Re-challenge After 1 week 1 day after 12 trial training in MWM, both vehicle and DOPS treatedmice responded comparably in a ‘challenge’ test. However 1 week laterthe vehicle mice, but not the DOPS treated mice, showed a significant reduced ability to find correct quadrant
  13. 13. L-DOPS increases CNS NA levels [NA], pg/mg wet wt 500 * 400 300 200 100 0 Control DOPS
  14. 14. L-DOPS reduces Thioflavin S plaques and is inversely correlated to NA levels in HC Hippocampus Frontal Cortex 200 100 Control TS plaques / field ControlTS plaques / field L-DOPS 150 L-DOPS 80 60 100 40 50 20 P = 0.0061 P = 0.1504 0 0 0 200 400 600 800 0 200 400 600 800 [NA], pg/mg [NA], pg/mg
  15. 15. L-DOPS neurotrophin mRNA expression 2.00Ratio mRNA (DOPS:Ctrl) * * 1.50 * * * * 1.00 * * 0.50 0.00
  16. 16. LC:NA signaling is also perturbed in MS and its rodent model EAE Simonini et al. (2010) ASN Neuro Polak et al (2011) Brain, in press
  17. 17. LC damage and inflammation is present in EAE Control EAE d d c c v v SCD SCDTH GFAP TH GFAP
  18. 18. LC damage and inflammation occurs in MS Increased GFAP staining LC DTgA Control TH GFAP Area covered (% field) 5.00 * * 4.00 DTg 3.00 2.00 1.00 0.00 Control MS Control MSB MS TH GFAP TH Neuronal hypertrophy 0.35 % cells in size bin ∗ 0.30 ∗ 0.25 0.20 DTg MS 0.15 0.10 0.05 HC 0.00 0 500 900 1300 1700 2100 2500 Size bin (µm2)
  19. 19. L-DOPS plus a NARI reduces clinical scores in EAE Clinical Score (mean +- se) 3.0 2.5 Control, n=10 2.0 1.5 * 1.0 ** DOPS/Atom, n=9 0.5 0.0 0 10 20 30 40 Days post MOG booster P= .0003 1 way Anova *, p < .05 **, P<0.01 vs day 17
  20. 20. ConclusionsLC neuronal stress and inflammation occur in the 5xFAD mouse model of AD Increasing CNS NA levels provides cognitive and pathological benefit in 5xFAD miceEffects on plaque burden may involve increased NEP/IDE Cognitive effects may involve increases in BDNF/Arc1 Dysfunction in the LC:NA system may be a feature of several neurological disorders
  21. 21. Acknowledgements Sergey Kalinin Paul PolakAlzheimer’s Association National MS Society NINDS, NIH VA Merit Grant

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