Perivascular drainage of Abeta and the pathogenesis

of Alzheimer’s Disease

Roxana Carare

University of SouthamptonUK

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

Immunohistochemistry, Aβ- brown

Patterns ofCerebral Amyloid

Angiopathy

Why does elimination of Aβ fail with age?

Why does elimination of Aβ fail with age?

Absorption of Aβ into

blood – LRP-1

Perivascular drainage of Aβ along basement

membranes of

capillaries and arteries

Perivascular

drainage of Aβ,

probably to cervical

lymph nodes

Capillary

Artery

Brain

Pathways for the elimination of Aβ

Enzymatic degradation of Aβ in artery wall

Discovered in Southampton, Carare et al, 2008

Discovered in Southampton, Carare et al, 2008

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Tracer

Artery

Capillary

Tracer

Perivascular distribution of particles of 0.02µm

Laminin

(Carare RO, 2002)

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Dextran in basement membranes (5min after injecting intracerebrally)

DextranLaminin

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)

Artery (thick wall and small lumen)

Vein (thin wall and big lumen)

Capillary

Aβ (dark brown)

Aβ (dark brown)

Injections with Aβ in naïve mice

Soluble monomeric Aβ40

(Atomic force microscopy)

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

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Immunization with amyloid-βHumans

Elan Pharmaceuticals clinical trials

- Aβ solubilised from plaques-Increased severity of CAA- Aβ 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 r

ed

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Hypothesis

Immunotherapy leads to the formation of immune complexes that become entrapped in the

perivascular drainage pathways

Interstitial fluid

Interstitial fluid

XX

Immune Complexes are deposited in capillary basement membranes and block perivascular drainage of solutes

arteriesveins

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Conclusions 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

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Failure of drainage of Soluble Aβ and other metabolites -Cognitive Decline

Aβ

Ageing of arteries

Brain

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FutureFutureHow 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

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

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Thank you. The team:

James Nicoll

Roy Weller

Hugh Perry Jessica Teeling

Delphine Boche

Anton PageAlex Langford

Meher LadEvghenia Katsoni

Baldeep SidhuSara Waters

Richard Reynolds

Wolfgang Hartig University of Leipzig

Karen HorsburghUniversity of Edinburgh

Dr Lynn AndrewsDr Guillaume Boucher

Cheryl Hawkes