Alzheimer’s Disease vs. Type 3 Diabetes 2006-04-20آ  Acetylcholine deficiency and loss of...

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Transcript of Alzheimer’s Disease vs. Type 3 Diabetes 2006-04-20آ  Acetylcholine deficiency and loss of...

  • Alzheimer’s Disease vs. Type 3 Diabetes:

    Role of Impaired Insulin Actions in the Brain

    de la Monte Laboratory Rhode Island Hospital Brown Medical School

    Providence, RI

  • Early Abnormalities in ADEarly Abnormalities in AD Metabolic:

    Reduced oxygen and glucose metabolism in the cerebral cortex

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

    Functional: Acetylcholine deficiency and loss of cholinergic neurons

  • Fundamental Problems Behind the Scene

    Fundamental Problems Behind the Scene

    Metabolic Not known. Few studies showed improved cognition with insulin administration or cognitive impairment in Type 1 diabetes

    Structural Gene mutations, oxidative stress including mitochondrial dysfunction, ischemia, unknown

    Functional Loss 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 Design Postmortem banked human brain tissue

    Different stages of AD or normal aging Brown Brain Bank Massachusetts General Hospital ADRC Duke 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+ Neurons Loss of Cholinergic Neurons in AD Linked to Death of Insulin & IGF-1 Receptor+ Neurons IN-R ChAT ChATIGF1-R

    AD ADControl Control

    IN-R + ChAT IGF1-R + ChAT

  • Increased Oxidative Stress in AD- Second Arm of Neurodegeneration Increased 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

    In su

    lin /1

    8S R

    at io

    (x 10

    -3 )

    P=0.03

    0

    1

    2

    3

    4

    5

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    7

    0

    1

    2

    3

    4

    5

    6

    7

    In su

    lin B

    in di

    ng (

    fm ol

    /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 In

    R /1

    8S R

    at io

    (x 10

    -3 ) P=0.007

    (x 10

    -3 )

    0

    10

    20

    30

    40

    50

    60

    70

    0

    10

    20

    30

    40

    50

    60

    70

    A PP

    /1 8S

    R at

    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

    IG F-

    II R

    /1 8S

    R at

    io

    (x 10

    -3 )

    0

    0.5

    1

    1.5

    2

    2.5

    0

    0.5

    1

    1.5

    2

    2.5

    IG F-

    II /1

    8S R

    at io

    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

    C hA

    T /1

    8S R

    at io

    P=0.0011

    0

    20

    40

    60

    80

    100

    120

    0

    20

    40

    60

    80

    100

    120

    IG F-

    II B

    in di

    ng (

    fm ol

    /m g) 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 Diabetes Impaired 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 responsiveness Develop 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

  • 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)

    Suzanne de la Monte, Brown Med. School Early Abnormalities in AD Fundamental Problems Behind the Scene Why Focus on Insulin Actions in the Brain? Questions Raised Study Design Decreased Growth Factor Receptor Expression in AD Decreased Growth Factor Gene Expression in AD Loss of Cholinergic Neurons in AD Linked to Death of Insulin & IGF-1 Receptor+ Neurons Increased Oxidative Stress in AD-Second Arm of Neurodegeneration Animal Model of Type 3 Diabetes/AD AD-Type Neurodegeneration in Experimental Type 3 Diabetes Model AD-Type Molecular Abnormalities in ic-STZ Model Increased DNA Damage/Oxidative Stress in ic-STZ Model Impaired Learning/Memory in Experimental Type 3 Diabetes Effects of Insulin & IGF Receptor Depletion on Neuronal Viability and Mitochondrial Function Hypothetical Scheme: Mechanisms of Neurodegeneration in AD Future Directions Credits