Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Mannix, Rebekah


Published on

Published in: Health & Medicine, Lifestyle
  • Be the first to comment

  • Be the first to like this

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
  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>