neurovascular regulation in health and disease
DESCRIPTION
Presentation made January 8, 2014 at the AlzForum live webinar: http://www.alzforum.org/webinars/neurovascular-underpinnings-alzheimers-dementia-0TRANSCRIPT
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Neurovascular Regulation in Health and Disease
Costantino Iadecola, M.D.Brain and Mind Research Institute
Weill Cornell Medical College
New York, NY, USA
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Brain vascularization and the neurovascular unit
Nat Neurosci Rev 5: 347, 2004
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ASTROCYTE
END-FEET
ENDOTHELIAL
CELL
FUNCTIONAL HYPEREMIA
TIGHT
JUNCTION
AUTOREGULATION
MEAN ARTERIAL PRESSURE (MMHG)50 150
CH
AN
GE
INC
BF AUTOREGULATED
RANGE
100
0
-50
+50
fMRI BOLD
FUNCTIONAL
IMAGING
MYOCYTE/PERI
CYTE
SYNAPTIC
ACTIVITY
Mechanisms of Cerebrovascular Regulation
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Multiple agents and cells mediate the increase in CBF
evoked by activation
NO
GABA
5HT
NE
ACh
DA
SP
NT
VIP
SOM
NPY
H+K+ NO, PGs
Glu
Ado
Central pathwaysInterneurons
Ca++NOS
COX-2 ATP
Ado
Glu
K+ siphoning
P450
PGs
COX
Ca++ waves
Ca++
EETs
Ca++
mGluR
ATP Ado
GJ
Arteriole
Brain Lang 102: 141-152, 2007
Astrocytes
Synaptic activity
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Perivascular
cells
CerebralArteriole Astrocyte
•••
Neuron
•
••
•
•
Myocyte/Pericyte Endothelium
Axon
The Neurovascular Unit: Beyond Blood Flow Regulation
Acta Neuropathol 120:287, 2010
Flow regulationBBB
exchangeImmune
surveillanceTrophic support(vascular niche)
Hypertension
Aging
Alzheimer
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Do Cerebrovascular Factors Contribute to Alzheimer’s Disease?
1. Cerebral blood flow is reduced in pre-symptomatic individuals at genetic riskfor AD, cerebral blood vessels are notnormal;
2. AD and cerebrovascular diseases sharesimilar risk factors (hypertension,dyslipidemia, obesity, etc.);
3. Small ischemic lesions aggravate thedementia in patients with mild ADpathology (The Nun Study).
Nat Rev Neurosci. 5:347, 2004
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Neuronaldysfunction
A peptides
Do vascular factors contribute to the
mechanisms of Alzheimer’s disease?
Cell. Mol. Neurobiol, 23:681, 2003
Vascular dysfunction
?
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Ringer or
AcetylcholineCBF
Neocortex
CPThal
Methods to investigate neurovascular regulation in mice
100
130
CB
F %
incr.
60
100
MA
Pm
mH
g
Stim.
Field potentials
Functional hyperemia, endothelium-dependent vasodilatation (acetylcholine, A23187),
smooth muscle function (adenosine)
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Neural and vascular CBF responses are attenuated inTg2576 mice at an early age
Whisker Stimulation Acetylcholine0
10
20
30
40
CB
F (%
incr
ease
)
Wild Type APP mice
*
* p<0.05; n=5/group
*
APP mice (age 3 months)
0 50 100 150 200-100
-50
0
50
100
150
Mean arterial pressure (mmHg)
CB
F (%
ch
ange
)
Wild type
APP mice
AJP 2002; 283:H315Nat Neurosci 2:157,1999; PNAS 97:9735, 2000
Smooth muscle function not affected
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Vascular dysregulation increases the
susceptibility to ischemic injury in Tg2576 mice
Time after MCA occlusion (min)
Infarct volume
J. Neurosci 76:1755, 1997
*Resting flow: Non-Tg: 148±1; Tg: 105±9 ml/100g/min
Intraischemic CBF
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AD patients have more strokes than age-matched controls
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NOX p22
p47
NADPH oxidase
Rac1p67
Serine
phosphorylation
R
PKC
Ligand
O2-•
Cellular dysfunction
NADPH oxidase is a major source of free radicals in cerebral blood vessels in AD models
Tg2576 mice
JCBFM 24:334, 2004
3-NT
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Developing APP mice deficient in NOX2
Tg2576 Tg2576/NOX2-/-
NOX2-/-Tg2576 X
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Nox2 deficiency rescues neurovascular dysfunction and behavioral deficits in Tg2576 mice
PNAS 105: 1347, 2008
Old (12-15 months)
ROS
(DHE)Tg2576/Nox2-/-Tg2576
Whisker stimulation
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
10
20
30A
*#
*
CB
F (
% in
cre
ase)
Acetylcholine
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
10
20
30B
*
#
*
CB
F (
% in
cre
ase)
Bradykinin
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
10
20
30C
*
#
*
CB
F (
% in
cre
ase)
Adenosine
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
10
20
30
40D
CB
F (
% in
cre
ase)
Young (3-4 months) Aged (12-15 months)
Whisker stimulation
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
10
20
30A
*#
*
CB
F (
% in
cre
ase)
Acetylcholine
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
10
20
30B
*
#
*
CB
F (
% in
cre
ase)
Bradykinin
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
10
20
30C
*
#
*
CB
F (
% in
cre
ase)
Adenosine
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
10
20
30
40D
CB
F (
% in
cre
ase)
Young (3-4 months) Aged (12-15 months)
Whisker stimulation
Young (3-4 months)
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
25
50
75
100
*
A
No
ve
l a
rm e
ntr
y (
%)
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
50
100
150B
* *
Tim
e i
n n
ov
el
arm
(s
ec
)
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
25
50
75
100
*
A
No
ve
l a
rm e
ntr
y (
%)
WT Nox2-/- Tg2576 Tg2576/Nox2-/-0
50
100
150B
* *
Tim
e i
n n
ov
el
arm
(s
ec
)Cognitive function
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Lipid raft
CD36
NOX p22
p47
NADPH oxidase
Rac1 p67
Serine phosphorylation
O2-•
A
Vav-GEF
Oxidativestress
Nucleusinflammation
NF-κB
CD36, an innate immunity receptor, binds A and activates inflammatory signaling
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Deletion of CD36 prevents the neurovascular
dysfunction and oxidative stress in Tg2576 mice
Radicals
PNAS 108: 5063, 2011
Tg2576 Tg2576/CD36-/-
Tg2576 X CD36-/-
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CD36 deletion reduces cerebral amyloid angiopathy, but not amyloid plaques
PNAS 110: 3089, 2013
No difference in plaque load or microglial density
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Deschaintre et al., Neurology 73: 674, 2009
Treatment of vascular risk factors slows down the
progression of dementia in patients with AD
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Cognitive impairment
•••
Perivascular
cell
CerebralArteriole Astrocyte
Neuron • ••
••
Neurovascular
dysfunction
Hypertension Alzheimer’s diseaseAging
USC
Health
•Oxidative stress
•Inflammation
The neurovascular unit in health and disease
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