1. Perivascular drainage of Abeta and the pathogenesis of Alzheimer’s Disease Roxana Carare University of Southampton UK

2.  The brain does not have conventional lymphatics  Alzheimer’s Disease: deposition of A β as plaques and in the walls of capillaries and arteries as cerebral amyloid angiopathy  Alzheimer ’ s disease: failure of elimination of Aβ from the aged brain

3. Immunohistochemistry, A β - brown Patterns of Cerebral Amyloid Angiopathy

4. Why does elimination of Aβ fail with age?

5. Absorption of A β into blood – LRP-1 Perivascular drainage of A β along basement membranes of capillaries and arteries Perivascular drainage of A β, probably to cervical lymph nodes Capillary Artery Brain Pathways for the elimination of A β Enzymatic degradation of A β in artery wall Discovered in Southampton, Carare et al, 2008

6. 6 Tracer Artery Capillary Tracer Perivascular distribution of particles of 0.02µm Laminin (Carare RO, 2002)

7. 7 Dextran in basement membranes (5min after injecting intracerebrally) Dextran Laminin Co-localisation Aβ: a natural tracer for drainage of interstitial fluid Soluble Tracers (dextran) drain along the basement membranes of capillaries and arteries in naïve mice (Carare et al, 2008)

8. Injections with A β in na ï ve mice Soluble monomeric A β40 (Atomic force microscopy)

9. Pulse Wave Contrary Wave Artery Ripples Contrary Wave Motive force Mathematical Modelling suggests that Contrary Waves drive Drainage of Interstitial Fluid and Solutes from the Brain Mechanisms to explain the reverse perivascular transport of solutes out of the brain. Schley D, Carare RO et al Journal of Theoretical Biology (2006) 238:962-974

10. 10 Immunization with amyloid-β Humans Elan Pharmaceuticals clinical trials - A β solubilised from plaques -Increased severity of CAA - A β solubilised from plaques -Increased severity of CAA Un-immunized AD (Aβ) Immunized AD (case 1, parietal lobe, Aβ) Nicoll et al, Nat Med (2003) Congo red

11. 11 Hypothesis Immunotherapy leads to the formation of immune complexes that become entrapped in the perivascular drainage pathways Interstitial fluid X X Immune Complexes are deposited in capillary basement membranes and block perivascular drainage of solutes arteries veins

12. 12 Conclusions Solutes drain along basement membranes of capillaries and arteries Particles expand the perivascular space Extracellular deposits of A β alter the distribution and drainage of solutes Immune complexes interfere temporarily with the drainage of solutes Perivascular drainage could be dependent on age and APOE genotype

13. 13 Failure of drainage of Soluble Aβ and other metabolites - Cognitive Decline AβAβ Ageing of arteries Brain

14. 14 Future How do basement membranes change with age? What are the nature of the interactions between A β and basement membranes? What role do cholesterol and APOE play in perivascular drainage? Therapeutic facilitation of perivascular drainage of A β along ageing artery walls How do basement membranes change with age? What are the nature of the interactions between A β and basement membranes? What role do cholesterol and APOE play in perivascular drainage? Therapeutic facilitation of perivascular drainage of A β along ageing artery walls

15. 15 Thank you. The team: James Nicoll Roy Weller Hugh PerryJessica Teeling Delphine Boche Anton Page Alex Langford Meher Lad Evghenia Katsoni Baldeep Sidhu Sara Waters Richard Reynolds Wolfgang Hartig University of Leipzig Karen Horsburgh University of Edinburgh Dr Lynn Andrews Dr Guillaume Boucher Cheryl Hawkes