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
Neurovascular Regulation in Health and Disease
Costantino Iadecola, M.D.Brain and Mind Research Institute
Weill Cornell Medical College
New York, NY, USA
Brain vascularization and the neurovascular unit
Nat Neurosci Rev 5: 347, 2004
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
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
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
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
Neuronaldysfunction
A peptides
Do vascular factors contribute to the
mechanisms of Alzheimer’s disease?
Cell. Mol. Neurobiol, 23:681, 2003
Vascular dysfunction
?
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)
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
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
AD patients have more strokes than age-matched controls
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
Developing APP mice deficient in NOX2
Tg2576 Tg2576/NOX2-/-
NOX2-/-Tg2576 X
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
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
Deletion of CD36 prevents the neurovascular
dysfunction and oxidative stress in Tg2576 mice
Radicals
PNAS 108: 5063, 2011
Tg2576 Tg2576/CD36-/-
Tg2576 X CD36-/-
CD36 deletion reduces cerebral amyloid angiopathy, but not amyloid plaques
PNAS 110: 3089, 2013
No difference in plaque load or microglial density
Deschaintre et al., Neurology 73: 674, 2009
Treatment of vascular risk factors slows down the
progression of dementia in patients with AD
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