Alzheimers vs Diabetes

7/29/2019 Alzheimers vs Diabetes

1/19

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


2/19

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


3/19

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?)


4/19

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


5/19

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?


6/19

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


7/19

Decreased Growth Factor Receptor

Expression in AD

Decreased Growth Factor Receptor

Expression in AD


8/19

Decreased Growth Factor GeneExpression in AD

Decreased Growth Factor GeneExpression in AD


9/19

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


10/19

Increased Oxidative Stress in AD-

Second Arm of Neurodegeneration

Increased Oxidative Stress in AD-

Second Arm of Neurodegeneration

C

APPNOX1 NOX3


11/19

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


12/19

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


13/19

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


14/19

Increased DNA Damage/OxidativeStress in ic-STZ Model

Increased DNA Damage/OxidativeStress in ic-STZ Model

8-OHdG

Control

4-HNE

ic-STZ


15/19

Impaired Learning/Memory in

Experimental Type 3 Diabetes

Impaired Learning/Memory in

Experimental Type 3 Diabetes

Morris Water Maze


16/19

Effects of Insulin &IGF ReceptorDepletion on

Neuronal Viabilityand Mitochondrial

Function

Effects of Insulin &IGF ReceptorDepletion on

Neuronal Viabilityand MitochondrialFunction


17/19

Hypothetical Scheme: Mechanisms of

Neurodegeneration in AD

Hypothetical Scheme: Mechanisms of

Neurodegeneration in AD


18/19

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


19/19

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)

Documents

Alzheimers vs Diabetes