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Alzheimers Disease vs.
Type 3 Diabetes:Role of Impaired Insulin Actions in the Brain
de la Monte Laboratory
Rhode Island HospitalBrown Medical School
Providence, RI
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Early Abnormalities in ADEarly Abnormalities in AD Metabolic:
Reduced oxygen and glucose metabolism in thecerebral cortex
Structural:
Dystrophic neuritesand neurofibrillary tangles,phospho-tau, ubiquitin
Amyloid- deposits
Functional:
Acetylcholine deficiency and loss of cholinergic
neurons
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Fundamental Problems
Behind the Scene
Fundamental Problems
Behind the Scene
MetabolicNot known. Few studies showed improved
cognition with insulin administration orcognitive impairment in Type 1 diabetes
StructuralGene mutations, oxidative stress including
mitochondrial dysfunction, ischemia,unknown
Functional Loss of cholinergic neurons (why?)
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Why Focus on Insulin
Actions in the Brain?
Why Focus on Insulin
Actions in the Brain?
Studies linked neuronal thread protein (NTP)over-expression in AD to neuronal insulin
resistance Ethanol-induced neurodegenerationcaused
by insulin resistance
Chemical knock-out of insulin producingcells in the brain causes AD-type dementia
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Questions RaisedQuestions Raised
Is Alzheimers disease associated withabnormalities in insulin-mediated function inthe brain?
Are abnormalities in insulin-mediated
functions detectable early in the course ofAD, and do the abnormalities worsen with
progression of neurodegeneration?
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Study DesignStudy Design Postmortem banked human brain tissue
Different stages of AD or normal agingBrown Brain Bank
Massachusetts General Hospital ADRC
Duke University
RNA (PCR) and Protein (Western blots
immunohistochemical staining, bindingassays)
Quantitative analysis of data
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Decreased Growth Factor Receptor
Expression in AD
Decreased Growth Factor Receptor
Expression in AD
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Decreased Growth Factor GeneExpression in AD
Decreased Growth Factor GeneExpression in AD
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Loss of Cholinergic Neurons in AD Linked to
Death of Insulin & IGF-1 Receptor+ Neurons
Loss of Cholinergic Neurons in AD Linked to
Death of Insulin & IGF-1 Receptor+ NeuronsIN-R ChAT ChATIGF1-R
AD ADControlControl
IN-R + ChAT IGF1-R + ChAT
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Increased Oxidative Stress in AD-
Second Arm of Neurodegeneration
Increased Oxidative Stress in AD-
Second Arm of Neurodegeneration
C
APPNOX1 NOX3
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Animal Model of Type 3 Diabetes/ADAnimal Model of Type 3 Diabetes/AD
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AD-Type Neurodegeneration in
Experimental Type 3 Diabetes Model
AD-Type Neurodegeneration in
Experimental Type 3 Diabetes ModelControl ic-STZ
Control
ic-STZ
ic-STZ
ic-STZ
APP-A
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AD-Type Molecular
Abnormalities in ic-STZ Model
AD-Type Molecular
Abnormalities in ic-STZ ModelIN/IGF-II IN-R/IGF-II-R IN/IGF-II Binding APP/ChAT
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
Insulin/18SRatio(x10
-3)
P=0.03
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
InsulinBinding(fmol/m
g)
P=0.0005
0
0.05
0.1
0.15
0.2
0.25
0.3
0
0.05
0.1
0.15
0.2
0.25
0.3
InR/18SRatio(x10-3)
P=0.007
(x10-3)
0
10
20
30
40
50
60
70
0
10
20
30
40
50
60
70
APP/18SRatio
P=0.0271
(x10-3)
0
0.02
0.04
0.06
0.08
0.1
0.12
0
0.02
0.04
0.06
0.08
0.1
0.12
IGF
-IIR/18SRatio(
x10-3)
0
0.5
1
1.5
2
2.5
0
0.5
1
1.5
2
2.5
IGF-II/18SRatio
P=0.006
(x
10-
3)
0
0.1
0.2
0.3
0.4
0.5
0
0.1
0.2
0.3
0.4
0.5
Ch
AT/18SRatio
P=0.0011
0
20
40
60
80
100
120
0
20
40
60
80
100
120
IGF-
IIBinding(fmol/mg)
P=0.0022
C STZC STZ C STZC STZ
I dDNA D /O id tiI dDNA D /O id ti
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Increased DNA Damage/OxidativeStress in ic-STZ Model
Increased DNA Damage/OxidativeStress in ic-STZ Model
8-OHdG
Control
4-HNE
ic-STZ
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Impaired Learning/Memory in
Experimental Type 3 Diabetes
Impaired Learning/Memory in
Experimental Type 3 Diabetes
Morris Water Maze
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Effects of Insulin &IGF ReceptorDepletion on
Neuronal Viabilityand Mitochondrial
Function
Effects of Insulin &IGF ReceptorDepletion on
Neuronal Viabilityand MitochondrialFunction
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Hypothetical Scheme: Mechanisms of
Neurodegeneration in AD
Hypothetical Scheme: Mechanisms of
Neurodegeneration in AD
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Future DirectionsFuture Directions
Utilize in vivo model to:Screen for novel therapeutic compounds to
restore insulin/IGF responsivenessDevelop methods to detect insulin/IGF-II
depletion and resistance in the CNS
Identify genes that mediate insulin resistance
and insulin gene depletion in the CNS
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CreditsCredits Eric Steen
Enrique Rivera
Nataniel Lester-Coll
Ming Tong
Alison Goldin
Noah Fulmer
Stephanie Soscia Ariel Cohen
Jack R. Wands
NIAAA, NCI (NIA-funded brain banks)
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