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?
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
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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 forceMathematical 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
Un-immunized AD (Aβ)
Immunized AD (case 1, parietal lobe, Aβ)
Nicoll et al, Nat Med (2003)
Cong
o re
d
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Hypothesis
Immunotherapy leads to the formation of immune complexes that become entrapped in the
perivascular drainage pathways
Interstitial fluid
X
Immune Complexes are deposited in capillary basement membranes and block perivascular drainage of solutes
arteries veins
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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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FutureHow 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 Page Alex LangfordMeher Lad
Evghenia KatsoniBaldeep Sidhu
Sara WatersRichard Reynolds
Wolfgang Hartig University of Leipzig
Karen HorsburghUniversity of Edinburgh
Dr Lynn AndrewsDr Guillaume Boucher
Cheryl Hawkes