Alzheimer’s Disease vs. Type 3 Diabetes:

Role of Impaired Insulin Actions in the Brain

de la Monte LaboratoryRhode Island HospitalBrown Medical School

Providence, RI

Early Abnormalities in ADEarly Abnormalities in ADMetabolic:

Reduced oxygen and glucose metabolism in the cerebral cortex

Structural:Dystrophic neurites and neurofibrillary tangles, phospho-tau, ubiquitinAmyloid-β deposits

Functional:Acetylcholine deficiency and loss of cholinergic neurons

Fundamental Problems Behind the Scene

Fundamental Problems Behind the Scene

MetabolicNot known. Few studies showed improved cognition with insulin administration or cognitive impairment in Type 1 diabetes

StructuralGene mutations, oxidative stress including mitochondrial dysfunction, ischemia, unknown

FunctionalLoss of cholinergic neurons (why?)

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 neurodegeneration caused by insulin resistance

Chemical knock-out of insulin producing cells in the brain causes AD-type dementia

Questions RaisedQuestions Raised

Is Alzheimer’s disease associated with abnormalities in insulin-mediated function in the brain?

Are abnormalities in insulin-mediated functions detectable early in the course of AD, and do the abnormalities worsen with progression of neurodegeneration?

Study DesignStudy DesignPostmortem banked human brain tissue

Different stages of AD or normal agingBrown Brain BankMassachusetts General Hospital ADRCDuke University

RNA (PCR) and Protein (Western blots immunohistochemical staining, binding assays)Quantitative analysis of data

Decreased Growth Factor Receptor Expression in AD

Decreased Growth Factor Receptor Expression in AD

Decreased Growth Factor Gene Expression in AD

Decreased Growth Factor Gene Expression in AD

Loss of Cholinergic Neurons in AD Linked to Death of Insulin & IGF-1 Receptor+ NeuronsLoss 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

Increased Oxidative Stress in AD-Second Arm of NeurodegenerationIncreased Oxidative Stress in AD-

Second Arm of Neurodegeneration

C

APPNOX1 NOX3

Animal Model of Type 3 Diabetes/ADAnimal Model of Type 3 Diabetes/AD

AD-Type Neurodegeneration in Experimental Type 3 Diabetes Model

AD-Type Neurodegeneration in Experimental Type 3 Diabetes Model

Control ic-STZ

Control

ic-STZ

ic-STZ

ic-STZ

APP-Aβ

AD-Type Molecular Abnormalities in ic-STZ Model

AD-Type Molecular Abnormalities in ic-STZ Model

IN/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

Insu

lin/1

8S R

atio

(x10

-3)

P=0.03

0

1

2

3

4

5

6

7

0

1

2

3

4

5

6

7

Insu

lin B

indi

ng (

fmol

/mg)

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

0.3In

R/1

8S R

atio

(x10

-3) P=0.007

(x10

-3)

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

APP

/18S

Rat

io

P=0.0271(x

10-3)

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

/18S

Rat

io

(x10

-3)

0

0.5

1

1.5

2

2.5

0

0.5

1

1.5

2

2.5

IGF-

II/1

8S R

atio

P=0.006

(x10

-3)

0

0.1

0.2

0.3

0.4

0.5

0

0.1

0.2

0.3

0.4

0.5

ChA

T/1

8S R

atio

P=0.0011

0

20

40

60

80

100

120

0

20

40

60

80

100

120

IGF-

II B

indi

ng (

fmol

/mg) P=0.0022

C STZC STZ C STZC STZ

Increased DNA Damage/Oxidative Stress in ic-STZ Model

Increased DNA Damage/Oxidative Stress in ic-STZ Model

8-OHdG

Control

4-HNE

ic-STZ

Impaired Learning/Memory in Experimental Type 3 DiabetesImpaired Learning/Memory in Experimental Type 3 Diabetes

Morris Water Maze

Effects of Insulin & IGF Receptor Depletion on Neuronal Viability and Mitochondrial Function

Effects of Insulin & IGF Receptor Depletion on Neuronal Viability and Mitochondrial Function

Hypothetical Scheme: Mechanisms of Neurodegeneration in AD

Hypothetical Scheme: Mechanisms of Neurodegeneration in AD

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

CreditsCreditsEric SteenEnrique RiveraNataniel Lester-CollMing TongAlison GoldinNoah FulmerStephanie SosciaAriel CohenJack R. WandsNIAAA, NCI (NIA-funded brain banks)