Perivascular drainage of Abeta and the pathogenesis of Alzheimer’s Disease

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 Aβ 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. Patterns of Cerebral Amyloid Angiopathy Immunohistochemistry, Aβ- brown

4. Why does elimination of Aβ fail with age?

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

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

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

8. Injections with Aβ in naïve mice Soluble monomeric Aβ40 (Atomic force microscopy)

9. Ripples Pulse Wave Artery Contrary Wave Contrary Wave Motive force Mathematical Modelling suggests thatContrary Wavesdrive 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 ROet al Journal of Theoretical Biology (2006) 238:962-974

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

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

12. Conclusions Solutes drain along basement membranes of capillaries and arteries Particles expand the perivascular space Extracellular deposits of Aβ 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. Aβ Brain Failure of drainage of Soluble Aβ and other metabolites -Cognitive Decline Ageing of arteries 13

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

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