Alzheimers 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 AD
Metabolic:
Reduced oxygen and glucose metabolism in the cerebral cortex

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

Functional:
Acetylcholine deficiency and loss of cholinergic neurons

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?

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 Raised
Is Alzheimers 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 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 Gene Expression in AD

Loss of Cholinergic Neurons in AD Linked to Death of Insulin & IGF-1 Receptor+ Neurons
IN-R IGF1-R ChAT ChAT

Control

AD

Control

AD

IN-R + ChAT

IGF1-R + ChAT

Increased Oxidative Stress in ADSecond Arm of Neurodegeneration

C

NOX1

NOX3

APP

Animal Model of Type 3 Diabetes/AD

AD-Type Neurodegeneration in Experimental Type 3 Diabetes Model

Control ic-STZ Control APP-A ic-STZ

ic-STZ

ic-STZ

AD-Type Molecular Abnormalities in ic-STZ Model

IN/IGF-II
Insulin/18S Ratio (x10-3)
InR/18S Ratio (x10-3)
0.14 0.12 0.1 0.08 0.06 0.04 0.02 0 P=0.03

IN-R/IGF-II-R
0.3 0.25 0.2 0.15 0.1 0.05 0 P=0.007

IN/IGF-II Binding
Insulin Binding (fmol/mg)
P=0.0005

APP/ChAT
APP/18S Ratio (x10-3)
70 60 50 40 30 20 10 0 P=0.0271

7 6 5 4 3 2 1 0

IGF-IIR/18S Ratio (x10-3)

IGF-II/18S Ratio (x10 )

2.5 2 1.5 1 0.5 0

0.12 0.1 0.08 0.06 0.04 0.02 0

120 100 80 60 40 20 0

ChAT/18S Ratio (x10-3)

P=0.006

IGF-II Binding (fmol/mg)

P=0.0022

-3

0.5 0.4 0.3 0.2 0.1 0

P=0.0011

C STZ

C STZ

C STZ

C STZ

Increased DNA Damage/Oxidative Stress in ic-STZ Model

8-OHdG 4-HNE

Control

ic-STZ

Impaired Learning/Memory in Experimental Type 3 Diabetes

Morris Water Maze

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

Hypothetical Scheme: Mechanisms of Neurodegeneration in AD

Future 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

Credits
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)