1. Visuo-spatial Memory in APP Transgenic Mice Mark Good School of Psychology Cardiff University

2. 90-95% are sporadic late-onset forms of AD 5% are early onset - Mendelian inheritance: Mutations  APP, PS1 & PS2 Early- & Late-onset Forms of AD: Amyloid hypothesis Amyloid Cascade Hypothesis Hardy & Allsop (1991)

3. APPswe Tg2676 model From : Kawarabayashi et al., 2001 K670N/M671L “Swedish” mutation No cell loss No Tangles

4. Tg2576 Mice Show Age-dependent Impairment in Spatial Memory Consistent: Spatial Memory Watermaze Radial Arm Maze T-Maze Arendash et al., 2001 Kotilinek et al., 2002 King & Arendash, 2002 Westerman et al., 2002 Ho et al., 2004 Lesne et al., 2006 Hippocampus

5. Room ARoom B FF Context/Room Discrimination II Aged Tg2576 do not show a global non-specific learning deficit Barnes, Hale & Good, Behav Neurosci, (2004) Intra-maze Visual Discrimination

6. What aspect(s) of spatial memory is impaired in Tg2576 mice? Navigation theories specify different strategies. O’Keefe & Nadel (1978) - allocentric vs egocentric HippocampusStriatum

7. Location Response F Hale & Good, 2008 Impaired Allocentric Learning but Spared Egocentric Learning in aged Tg2576 mice

8. How does the APP mutation influence spatial memory in Tg2576 mice? Object Exploration Paradigm Exploration reflects a mismatch between current sensory experience and a stored representation(memory) or a prior event. 1. Object Memory? 2. Object-Location Memory?

9. Testing Object and Location Memory in Mice Exposure Test D ? 10 min

10. Intact Object Memory in Aged Tg2576 Mice Hale & Good, Behav Neurosci, (2005)

11. Sample Test Object Location Memory

12. Hale & Good, Behav Neurosci 2005 Impaired Object Location Memory

13. Dissociable components of object location memory Object-in-place Object-location (Dix & Aggleton, 1999) ? Independent of object identity

14. a b c d a c b d Sample Test Experiment 1 a b c d a d b c a b c d a d f e Experiment 2 a b c d Experiment 3 b a d c d b c a a e f d a c b d Novelty Familiar object -> familiar location Familiar object -> novel location Novel object and a novel location a b c d Familiar object -> novel location Familiar object -> familiar location Good & Hale, Behav Neurosci. 2007

15. a e f d a c b d Novelty Detection Experiment 1 Good & Hale, Behav Neurosci. 2007

16. a e f d a c b d a b c d a c b d Objects moved to familiar location Experiment 1 Good & Hale, Behav Neurosci. 2007

17. a b c d a d b c a d f e Objects moved to a novel location Experiment 1 Experiment 2 Good & Hale, Behav Neurosci. 2007

18. a b c d a d b c a d f e Objects moved to a novel location Experiment 1 Experiment 2 Good & Hale, Behav Neurosci. 2007

19. a b c d a d b c a d f e Objects moved to a novel location Experiment 1 Experiment 2 Good & Hale, Behav Neurosci. 2007

20. Objects moved to novel locations Experiment 3 Good & Hale, Behav Neurosci. 2007 AB CD AB CD SampleTest

21. AB CD A B C D Objects moved to familiar locations Experiment 3 Good & Hale, Behav Neurosci. 2007 SampleTest Prediction: Tg2576 Familiar Locations Tg2576 = WT: Object -> Novel Locations

22. Specific impairment in object-in-place memory in Tg2576 mice Experiment 3 a b c d b a d c d b c a a b c d Good & Hale, Behav Neurosci. 2007 NovelFamiliar

23. Spared Spatial Memory Memory for object-locations (independent of object identity) Impaired Spatial Memory Memory for object-in-place associations (conjunctive representation of object and place) Computational/Anatomical Locus? Characteristics of Object Spatial Memory in Tg2576 mice

24. Impairments in entorhinal/dentate gyrus inputs to the hippocampus may underlie the deficits in spatial memory in Tg2576 mice

25. Impairments in dentate gyrus spine density observed early during development in Tg2576 mice Jacobsen et al., 2006, PNAS,103 (13), 5161-6 WTTg2576

26. Hernandez-Rabaza, et al.,, 2007 Dentate Gyrus Lesions in Rats Impairs T-maze but Spares Object Recognition and Object Location Memory Dentate Gyrus Lesions Disrupt T-Maze but not Recognition Memory

27. Conclusions Profile of learning processes in Tg2576 mice 1.Impaired place learning/navigation in Tg2576. 2.Not a global cognitive impairment. 3.Integration of object/landmark identity and location information is impaired in Tg2576 mice. Speculation Disruption of entorhinal/dentate gyrus synaptic connections/plasticity supporting pattern separation may be amongst the early pathological changes underlying memory impairments in AD.

28. Thanks to: Karen Ashe Paul Chapman (GSK?) Philip Barnes Gemma Hale

29. Conclusion Impaired spatial memory despite intact landmark recognition deIpolyi, et al., 2007: Neurology, 69,986-997 Characteristics of Spatial Memory in early AD patients MCI & Mild AD patients >70 yo Hallway Navigation Task

30. D B C A A B C D Place & Order Good, Hale & Staal,Behav Neurosci (2007) Episodic-like Memory is impaired in aged Tg2576 Mice Deficit reflects impaired spatial (object-location) memory