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The role of neuroinflammation in
the determination of regional and
neuronal vulnerability in
Alzheimer’s disease
Holly M. Brothers & Gary L. Wenk
Department of Psychology
The Ohio State University
Nothing to Disclose
Studies in our laboratory
demonstrate that regional and
cellular vulnerability in the
brain are influenced by an
interaction between:
neuroinflammation, duration
of inflammation, and gender.
What initiates neuroinflammation?
What are its consequences?
Microglial activation is an early event
in the pathogenesis of AD that
appears in brain regions that later
show the greatest degree of atrophy.
Mutant
Proteins
Inflammation
Synaptic
Loss/
Neuronal
Death
Dementia
Symptoms
Cagnin et al., 2001
Chronic neuroinflammation model
Infusion of lipopolysaccharide (LPS, 0.15µl/hr,
6µg/day) into the IVth ventricle or basal forebrain
cannula tract
Regional microglia activation
LPS 21 days → activated microglia in the
hippocampus and temporal lobe.
2 Days
21 Days
aCSF + Sal, 4 weeks
LPS + Sal, 4 weeks
Is there a pathological consequence?
Total Number of Neurons (x104)
Fewer cresyl violet
stained cells counted
by stereology in
entorhinal cortex
layers II and III of
rats infused with LPS
for 37 days
9
8
7
*
6
*
5
4
3
2
1
0
aCSF
LPS
Hauss-Wegrzyniak et al., 2002
Is there a pathological consequence?
Volumetric MRI analysis revealed that 42 days of
LPS infusion caused a significant shrinkage of the
temporal lobes and hippocampus and increase in the
volume of the lateral ventricles.
aCSF
LPS
Hauss-Wegrzyniak et al., 2000
Is there a functional consequence?
Impaired
LTP
induction
in vivo in
dentate gyrus
of rats
infused with
LPS for 37
days
Hauss-Wegrzyniak et al., 2002
What underlies a loss of LTP?
Glutamate is necessary for LTP
Glutamate dysfunction disrupts LTP
Glutamate → NMDAR activation → Ca++ entry → Arc induction
Mg+
Glutamatergic
neuron
Ca++
Arc
5 min
Arc
in DG
Rosi et al., 2005
30 min
Chronic neuroinflammation activates microglia
(blue) and over-activates Arc (red)
a-CSF
Arc + hippocampal
neurons:
aCSF: ~2%
LPS: ~4%
LPS
Rosi et al., 2005
What other regions are vulnerable to chronic
neuroinflammation?
LPS infused into the
nucleus basalis
magnocellularis (14, 37,
74 or 112 days) produced
a time-dependent, but
not dose-dependent,
decline in the number of
Choline acetyltransferase
(ChAT)-immunoreactive
cells.
Willard et al., 1999
SN dopaminergic neurons are also
vulnerable to chronic inflammation
aCSF + Sala
LPS + Salb
Does Gender influence the response
to neuroinflammation?
Number of Activated Microglia
Female rats infused 42 days with LPS have ~1/2 the
number of activated microglia as males.
Estrogen replacement did not protect.
‡
1600
1400
‡
1200
1000
+#
800
600
400
200
0
aCSF LPS aCSF LPS aCSF LPS
Intact
Marriott et al., 2002
OVX
OVX +
Estrogen
Microglia activation correlates with impaired water
maze performance (r = 0.481, p<0.03)
Neuroinflammation did not impair the performance of
intact females
Path Length (cm)
1200
1000
800
600
aCSF OVX
LPS
aCSF
400
200
Mean + SEM
0
1
2
3
Day of Testing
4
Marriott et al., 2002
In the absence of ovaries:
• Chronic neuroinflammation impaired performance.
• Chronic estrogen impaired performance.
• Together, ovariectomy and LPS were synergistic.
Path Length (cm)
1200
+
1000
800
*
600
400
200
LPS OVX + E2
LPS OVX
aCSF OVX + E2
aCSF OVX
LPS
aCSF
Mean + SEM
0
1
2
3
Day of Testing
4
Marriott et al., 2002
Regional and cellular vulnerability is influenced by
neuroinflammation, time and gender.
• Distribution of activated microglia changes over time and
concentrates within regions prone to neurodegeneration.
• The loss of forebrain acetylcholine neurons and is time-dependent.
• Chronic neuroinflammation is likely responsible for the
selective vulnerability of specific neural systems and brain
regions associated with age-related neurodegenerative changes.
• Female rats show no neuroinflammation-induced cognitive
impairment unless ovarian function is lost.
Dr. Beatrice
Dr. Susanna
Dr. Gary L.
Hauss-Wegrzyniak
Rosi
Wenk
ICAD 2009
Dr. Lisa
Marriott
Dr. Yannick
Marchalant
Supported by NIA
Holly M.
Brothers
Contact: [email protected]