Presentation made January 8, 2014 at the AlzForum live webinar: http://www.alzforum.org/webinars/neurovascular-underpinnings-alzheimers-dementia-0

1. Neurovascular Regulation in Health and
Disease
Costantino Iadecola, M.D.
Brain and Mind Research Institute
Weill Cornell Medical College
New York, NY, USA

2. Brain vascularization and the neurovascular unit
Nat Neurosci Rev 5: 347, 2004

3. Mechanisms of Cerebrovascular Regulation
FUNCTIONAL HYPEREMIA
SYNAPTIC
ACTIVITY
ASTROCYTE
TIGHT
JUNCTION
END-FEET
MYOCYTE/PERI
CYTE
FUNCTIONAL
ENDOTHELIAL
CELL
IMAGING
AUTOREGULATION
CHANGE IN CBF
+50
AUTOREGULATED
RANGE
0
-50
50
100
150
MEAN ARTERIAL PRESSURE (MMHG)
fMRI BOLD

4. Multiple agents and cells mediate the increase in CBF
evoked by activation
Synaptic activity
Ca++
NOS
COX-2
Glu
GJ
mGluR
ATP
Ado
Glu
K+
H+
NO, PGs
Ado
Ca++ waves
Ca++
Central pathways
Interneurons
Ca++
PGs
COX
EETs
P450
Astrocytes
ATP
Ado
K+ siphoning
Arteriole
NO
GABA
5HT
NE
ACh
DA
SP
NT
VIP
SOM
NPY
Brain Lang 102: 141-152, 2007

5. The Neurovascular Unit: Beyond Blood Flow
Regulation
Myocyte/PericyteAging
Endothelium
Cerebral
Arteriole
Perivascular
cells
Hypertension
••
••
•
Astrocyte
•• •
Alzheimer
Neuron
Flow regulation
BBB
exchange
Axon
Immune
surveillance
Trophic support
(vascular niche)
Acta Neuropathol 120:287, 2010

6. Do Cerebrovascular Factors Contribute to
Alzheimer’s Disease?
1. Cerebral blood flow is reduced in presymptomatic individuals at genetic risk
for AD, cerebral blood vessels are not
normal;
2. AD and cerebrovascular diseases share
similar risk factors (hypertension,
dyslipidemia, obesity, etc.);
3. Small ischemic lesions aggravate the
dementia in patients with mild AD
pathology (The Nun Study).
Nat Rev Neurosci. 5:347, 2004

7. Do vascular factors contribute to the
mechanisms of Alzheimer’s disease?
A peptides
?
Neuronal
dysfunction
Vascular
dysfunction
Cell. Mol. Neurobiol, 23:681, 2003

8. Methods to investigate neurovascular regulation in mice
Ringer or
Acetylcholine
Neocortex
100
MAP
mmHg
Field potentials
CBF
CBF % incr.
60
CP
130
Thal
100
Stim.
Functional hyperemia, endothelium-dependent vasodilatation (acetylcholine, A23187),
smooth muscle function (adenosine)

9. Neural and vascular CBF responses are attenuated in
Tg2576 mice at an early age
APP mice (age 3 months)
Wild Type
100
* p<0.05; n=5/group
30
20
*
*
10
0
150
APP mice
CBF (% change)
CBF (% increase)
40
Wild type
APP mice
50
0
-50
Whisker Stimulation
Acetylcholine
-100 0
50
100
150
Mean arterial pressure (mmHg)
Nat Neurosci 2:157,1999; PNAS 97:9735, 2000
Smooth muscle function not affected
200
AJP 2002; 283:H315

10. Vascular dysregulation increases the
susceptibility to ischemic injury in Tg2576 mice
Intraischemic CBF
Infarct volume
Time after MCA occlusion (min)
*Resting flow: Non-Tg: 148±1; Tg: 105±9 ml/100g/min
J. Neurosci 76:1755, 1997

11. AD patients have more strokes than age-matched controls

12. NADPH oxidase is a major source of free radicals
in cerebral blood vessels in AD models
Tg2576 mice
Ligand
3-NT
NADPH oxidase
NOX
p22
R
Serine
phosphorylation
p47
Rac1
p67
O2-•
Cellular dysfunction
JCBFM 24:334, 2004
PKC

13. Developing APP mice deficient in NOX2
Tg2576
Tg2576
X
NOX2-/-
Tg2576/NOX2-/-

14. Nox2 deficiency rescues neurovascular dysfunction
and behavioral deficits in Tg2576 mice
Old (12-15 months)
Nox2-/WT
10
0
10
0
Tg2576
*
*
#
10
#
*
#
*
25
0WT 0
100
50
0
Adenosine
Adenosine
30
Tg2576/Nox2-/-
20
10
50
0
Tg2576
WT Nox2-/- Nox2-/Tg2576 Tg2576/Nox2-/- WT
Nox2-/-WT Nox2-/- Tg2576 Tg2576/Nox2-/Tg2576 Tg2576/Nox2-/- Tg2576/Nox2-/-
D 40
30
(DHE)
*
#
B 150
100
*
*
D 40
ROS
*
*
B 150
Time in novel arm (sec)
25
20
50
Tg2576/Nox2-/Tg2576 Tg2576/Nox2-/WT
Bradykinin
Bradykinin
20
*
Tg2576
Nox2-/-
50
75
Acetylcholine
CognitiveAcetylcholine
function
Time in novel arm (sec)
#
CBF (% increase)
*
20
CBF (% increase)
0
CBF (% increase)
WT
C 30
10
*
10
C 30
20
*
#
CBF (% increase)
0
*
75
CBF (% increase)
10
20
Novel arm entry (%)
CBF (% increase)
20
CBF (% increase)
Whisker stimulation 100B 30 100 30
Whisker stimulation
A B
A
A 30Whisker stimulation
Novel arm entry (%)
A 30
CBF (% increase)
Young (3-4 months)
20
PNAS 105: 1347, 2008
10
WT
Nox2

15. CD36, an innate immunity receptor, binds A and
activates inflammatory signaling
CD36
A
NOX
Lipid raft
Nucleus
Serine
phosphorylation
p47
Vav-GEF
NF-κB
NADPH oxidase
p22
Rac1
p67
•
O2-
inflammation
Oxidative
stress

16. Deletion of CD36 prevents the neurovascular
dysfunction and oxidative stress in Tg2576 mice
Tg2576
Tg2576
X
CD36-/-
Radicals
Tg2576/CD36-/-
PNAS 108: 5063, 2011

17. CD36 deletion reduces cerebral amyloid
angiopathy, but not amyloid plaques
No difference in plaque load or microglial density
PNAS 110: 3089, 2013

18. Treatment of vascular risk factors slows down the
progression of dementia in patients with AD
Deschaintre et al., Neurology 73: 674, 2009

19. The neurovascular unit in health and disease
Hypertension
Alzheimer’s disease
Aging
USC
Health
Perivascular
cell
Neurovascular
dysfunction
•Oxidative stress
Cerebral
Arteriole
Neuron
•
•• ••
•••
Cognitive
impairment
Astrocyte
•Inflammation