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Mannix, Rebekah

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Mannix, Rebekah

  1. 1. Detrimental Effect of Genetic Inhibition of β-Site APP Cleaving Enzyme 1 on Functional Outcome after Controlled Cortical Impact In Young Adult Mice Rebekah Mannix M.D, MPH
  2. 2. Background <ul><li>Amyloid Beta (Aβ) is a 40-42 amino acid peptide implicated in synaptic dysfunction and cell death in Alzheimer’s Disease (AD) </li></ul><ul><li>Aβ protein is generated by successive action of the β and γ secretases on amyloid precursor protein </li></ul>
  3. 3. From http://www.rndsystems.com/cb_detail_objectname_WI00_BaceAlzheimers.aspx
  4. 4. Background <ul><li>Epidemiological studies have demonstrated an association between a history of Traumatic Brain Injury (TBI) and the development of AD later in life* </li></ul><ul><li>Post-mortem studies have demonstrated AD like deposits of Aβ in as many as 30% of TBI victims** </li></ul>*Graves et al Am J Epidemiol, 1990; Mortimer et al Neurology , 1985; Van Den Heuvel Prog Brain Res , 2005 **Roberts et al J Neurol Neurosurg Psychiatry, 1994
  5. 5. Background <ul><li>The pathological and epidemiological associations of AD and TBI have led to interest in strategies targeting Aβ after TBI </li></ul><ul><li>A recent landmark study by Loane et al. (2009) demonstrated that genetic inhibition of Bace1 derived Aβ improved histopathological and functional outcomes after TBI in aged mice </li></ul>
  6. 7. Background <ul><li>The majority of severe brain trauma patients are young adults between the ages of 18 and 40 </li></ul>
  7. 8. Relevance of Aβ across the spectrum of age? Roberts et al J Neurol Neurosurg Psychiatry, 1994 Control patients TBI patients
  8. 9. Relevance of Aβ across the spectrum of age? <ul><li>We have recently shown that </li></ul><ul><ul><li>Adult APOE4 transgenic mice have progressive decline in cognitive function and prolonged elevations of soluble Aβ after TBI* </li></ul></ul><ul><ul><li>In contrast, immature APOE4 mice quickly remediate elevations of soluble Aβ after TBI* </li></ul></ul><ul><ul><li>Injury in the immature period improves long-term Aβ clearance in APOE4 animals when compared to naïve control APOE4 mice* </li></ul></ul>*Mannix et al JCBFM , 2011
  9. 10. Relevance of Aβ across the spectrum of age? <ul><li>Experimental models also have shown that </li></ul><ul><ul><li>Aβ toxicity increases with aging in cultured neurons </li></ul></ul><ul><ul><li>Microglia clearance of Aβ decreases with aging </li></ul></ul><ul><ul><li>*Brewer Neurobiol Aging, 1998 </li></ul></ul><ul><ul><li>**Hickman et al J Neurosci, 2008 </li></ul></ul>
  10. 11. Is Bace1 derived Aβ a therapeutic target across the spectrum of age?
  11. 12. Hypothesis <ul><li>Following controlled cortical impact, genetic antagonism of Bace1 will not improve functional and histopathological outcomes in young adult mice </li></ul>
  12. 13. Experimental Protocol <ul><li>Male (2-3 months old) mice </li></ul><ul><ul><li>32 Bace1 knockout ( Bace1 -/- ) </li></ul></ul><ul><ul><li>42 wild type Bace1 +/+ (C57Bl/6) mice </li></ul></ul><ul><li>Controlled cortical impact (velocity 6 m/s, and impact depth of 0.6 mm) or sham injury </li></ul>
  13. 14. Experimental Protocol <ul><li>Soluble Aβ 40 in Bace1 −/− and Bace1 +/+ 48 hrs after both CCI and sham injury in ipsilateral hemisphere </li></ul><ul><li>Motor (wire grip) days 1-7 after injury </li></ul><ul><li>Morris Water Maze days 7-10 after injury </li></ul><ul><li>Lesion volume and hippocampal loss day 21 after injury </li></ul>
  14. 15. Results – Aβ 40 levels Sham vs. injured Bace1 +/+ mice (n= 6-11/group, p = 0.03) Sham vs. injured Bace1 -/- mice (n = 4-6/group, p=0.14)
  15. 16. Results - Wire Grip Injured Bace1 -/- compared to injured Bace1 +/+ (n=17-18/group p = 0.003)
  16. 17. Results – Morris Water Maze Bace 1 -/- mice performed significantly worse than sham-injured Bace 1 -/- mice (n= 6-8/group sham injury, 14-18 group CCI , p= 0.0029)
  17. 18. Results: Probe Trials Injured Bace1 -/- vs. Bace1 +/+ mice (p=0.0009)
  18. 19. Results n=8/group
  19. 20. Conclusions <ul><li>These data suggest that further studies are needed to evaluate therapies targeting Bace1 after TBI </li></ul><ul><li>Targeting Bace1 derived Aβ might not be appropriate across the spectrum of age and injury </li></ul>
  20. 21. Limitations <ul><li>Different results from those previously reported </li></ul><ul><ul><li>Level of Injury </li></ul></ul><ul><ul><li>Days of testing </li></ul></ul><ul><ul><li>Tests used </li></ul></ul>
  21. 22. Next Steps - Aβ rescue 200 pmol Aβ 40 ICV immediately after injury
  22. 23. Next Steps <ul><li>Future studies </li></ul><ul><ul><li>Dose/response Aβ replacement in Bace1 −/− and Bace1 +/+ animals </li></ul></ul><ul><ul><li>Pharmacologic approach Aβ inhibition </li></ul></ul>
  23. 24. Acknowledgments <ul><li>Funded by: K12 HD052896-01A1 and the Charles Hood Foundation </li></ul><ul><li>Mentor: Mike Whalen </li></ul><ul><li>Lab technicians: Jimmy Zhang, Chris Lee and Juyeon Park </li></ul>
  24. 25. Thank you
  25. 26. Non-zero Aβ Levels <ul><li>Other β-secretases </li></ul><ul><ul><li>cathepsin B +D </li></ul></ul>
  26. 27. Baseline differences? <ul><li>No differences in Bace1 −/− and Bace1 +/+ sham injured animals </li></ul><ul><li>Prior studies </li></ul><ul><ul><li>abnormal locomotor activation </li></ul></ul><ul><ul><li>slower swimming speed </li></ul></ul><ul><ul><li>abnormal spatial learning   </li></ul></ul><ul><ul><li>decreased grip strength </li></ul></ul><ul><ul><li>abnormal myelin sheath morphology in 2-month old mice </li></ul></ul>

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