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1/5/2015
Biomedical Research Models, Inc.
Contract Discovery and Preclinical Research
Alzheimer’s Disease
1/5/2015
Clinical Symptoms of AD
• Memory loss that disrupts daily
life
• Changes in planning of solving
problems
• Difficulty completing familiar
tasks at home, at work or at
leisure
• Confusion with time or place
• Trouble understanding visual
images and spatial relationships
• New problems with words in
speaking or writing
• Misplacing things and losing the
ability to retrace steps
• Decreased or poor judgment
• Withdrawal from work or social
activities
• Changes in mood and
personality
1/5/2015
Risk Factors of AD
• Age
• Genetics
• Insulin resistance
• Hyperglycemia
• Inflammation
• Oxidative stress
1/5/2015
7 Stages of Alzheimer’s
Disease
7 Stages of AD
• 1 – no impairment
• 2 – very mild decline
• 3 – mild decline
• 4 – moderate decline (mild to early stage)
• 5 – moderately server decline (moderate to mid-
stage)
• 6 – sever decline (moderately severe to mid-
stage)
• 7 – very severe decline (severe or late state)
1/5/2015
Comparison between BB/Wor-
and BBZDR/Wor-Diabetic Rats
1. Neuronal loss
2. Neuronal apoptosis
3. Alterations of various factors mediating apoptotic
activity:
- Apoptosis-regulating proteins
- Perturbation of IGF system
- Activation of Fas/NGF-R.p75
- Oxidative stress: PARP, 8-OHdG
- Caspase activation
1/5/2015
CA1
CA2
CA3
CA4
DF
Sub
Neuronal densities in type 1 vs. type 2
diabetic BB/Wor ratsNeuronaldensity(numbers/mm2)
0
500
1000
1500
2000
2500
3000
3500
CA1 CA2 CA3 CA4
*** *
* †
* p < 0.05, *** p < 0.001 vs. control, † p < 0.05 vs. BB/Wor
Control (n=4)
BBZDR/Wor (n=4)
BB/Wor (n=4)
1/5/2015
a). Active caspase-3
*
0
1.0
2.0
3.0
Control BB/Wor BBZDR
15 kD
22 kD
-17 kD
b). Caspase 12
0
1.0
2.0
3.0
4.0 *
†
Control BB/Wor BBZDR
51 kD
62 kD
-55 kD
Relativedensity(Arbitralunit)
Relativedensity(Arbitralunit)
* p < 0.05 vs. control; † p < 0.05 vs. BB/Wor
Expression of caspases in type 1 vs.
type 2 diabetic BB/Wor rats
1/5/2015
* p < 0.05, ** p < 0.01 vs. control. † p < 0.05 vs. BB/Wor
Bax
Control BB/Wor BBZDR /Wor
Bcl-xL
Control BB/Wor BBZDR/Wor
0
1.0
2.0
3.0
**
†
0
0.5
1.0
1.5
Relativedensity(Arbitralunit)
Apoptosis- regulating proteins in type 1 vs.
type 2 diabetic BB/Wor rats
(hippocampus, 8 months)
1/5/2015
Splicing of the transmembranous
APP-molecule
APP
Cell-membrane
-secretase
-secretase
I-40 AS
(vessels)
I-42 AS
(neurons)
1/5/2015
APP Frontal Cortex
Control
BB/W
BB/ZDR Cont BB/W BB/Z
0.0
1.0
2.0
3.0 **
**
** p < 0.005 vs. control
1/5/2015
β – Secretase Frontal Cortex
Control
BB/W
BB/ZDR
Cont BB/W BB/Z
0.0
1.0
2.0 *
**
* p < 0.05, ** p < 0.005 vs. control
1/5/2015
Control
BBW
BBZ
Aβ 1-42 Frontal Cortex
Cont BB/W BB/Z
*
**
*
0.0
2.0
3.0
1.0
2.0
* p < 0.05, ** p < 0.005 vs. control
1/5/2015
Formation of Paired Helical
Filaments (NFT)
β-amyloid
Adap78
 Calcineurin
Hyperphosphorylated Tau
 Caspase 3 Spliced Tau
 ; β
Enmark and Davis, 2002
APOPTOSIS
Apoptosis
inducing
elements
Cell death
1/5/2015
References
• Li ZG., Zhang W., Sima AA. Alzheimer-like
changes in rat models of spontaneous diabetes.
Diabetes 2007 Oct;56(10):2650.
• Sima AA. Encephalopathies: the emerging
diabetic complications. Acta Diabetologica
August 2010.
14

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Alzheimer's Animal Model

  • 1. 1/5/2015 Biomedical Research Models, Inc. Contract Discovery and Preclinical Research Alzheimer’s Disease
  • 2. 1/5/2015 Clinical Symptoms of AD • Memory loss that disrupts daily life • Changes in planning of solving problems • Difficulty completing familiar tasks at home, at work or at leisure • Confusion with time or place • Trouble understanding visual images and spatial relationships • New problems with words in speaking or writing • Misplacing things and losing the ability to retrace steps • Decreased or poor judgment • Withdrawal from work or social activities • Changes in mood and personality
  • 3. 1/5/2015 Risk Factors of AD • Age • Genetics • Insulin resistance • Hyperglycemia • Inflammation • Oxidative stress
  • 4. 1/5/2015 7 Stages of Alzheimer’s Disease 7 Stages of AD • 1 – no impairment • 2 – very mild decline • 3 – mild decline • 4 – moderate decline (mild to early stage) • 5 – moderately server decline (moderate to mid- stage) • 6 – sever decline (moderately severe to mid- stage) • 7 – very severe decline (severe or late state)
  • 5. 1/5/2015 Comparison between BB/Wor- and BBZDR/Wor-Diabetic Rats 1. Neuronal loss 2. Neuronal apoptosis 3. Alterations of various factors mediating apoptotic activity: - Apoptosis-regulating proteins - Perturbation of IGF system - Activation of Fas/NGF-R.p75 - Oxidative stress: PARP, 8-OHdG - Caspase activation
  • 6. 1/5/2015 CA1 CA2 CA3 CA4 DF Sub Neuronal densities in type 1 vs. type 2 diabetic BB/Wor ratsNeuronaldensity(numbers/mm2) 0 500 1000 1500 2000 2500 3000 3500 CA1 CA2 CA3 CA4 *** * * † * p < 0.05, *** p < 0.001 vs. control, † p < 0.05 vs. BB/Wor Control (n=4) BBZDR/Wor (n=4) BB/Wor (n=4)
  • 7. 1/5/2015 a). Active caspase-3 * 0 1.0 2.0 3.0 Control BB/Wor BBZDR 15 kD 22 kD -17 kD b). Caspase 12 0 1.0 2.0 3.0 4.0 * † Control BB/Wor BBZDR 51 kD 62 kD -55 kD Relativedensity(Arbitralunit) Relativedensity(Arbitralunit) * p < 0.05 vs. control; † p < 0.05 vs. BB/Wor Expression of caspases in type 1 vs. type 2 diabetic BB/Wor rats
  • 8. 1/5/2015 * p < 0.05, ** p < 0.01 vs. control. † p < 0.05 vs. BB/Wor Bax Control BB/Wor BBZDR /Wor Bcl-xL Control BB/Wor BBZDR/Wor 0 1.0 2.0 3.0 ** † 0 0.5 1.0 1.5 Relativedensity(Arbitralunit) Apoptosis- regulating proteins in type 1 vs. type 2 diabetic BB/Wor rats (hippocampus, 8 months)
  • 9. 1/5/2015 Splicing of the transmembranous APP-molecule APP Cell-membrane -secretase -secretase I-40 AS (vessels) I-42 AS (neurons)
  • 10. 1/5/2015 APP Frontal Cortex Control BB/W BB/ZDR Cont BB/W BB/Z 0.0 1.0 2.0 3.0 ** ** ** p < 0.005 vs. control
  • 11. 1/5/2015 β – Secretase Frontal Cortex Control BB/W BB/ZDR Cont BB/W BB/Z 0.0 1.0 2.0 * ** * p < 0.05, ** p < 0.005 vs. control
  • 12. 1/5/2015 Control BBW BBZ Aβ 1-42 Frontal Cortex Cont BB/W BB/Z * ** * 0.0 2.0 3.0 1.0 2.0 * p < 0.05, ** p < 0.005 vs. control
  • 13. 1/5/2015 Formation of Paired Helical Filaments (NFT) β-amyloid Adap78  Calcineurin Hyperphosphorylated Tau  Caspase 3 Spliced Tau  ; β Enmark and Davis, 2002 APOPTOSIS Apoptosis inducing elements Cell death
  • 14. 1/5/2015 References • Li ZG., Zhang W., Sima AA. Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes 2007 Oct;56(10):2650. • Sima AA. Encephalopathies: the emerging diabetic complications. Acta Diabetologica August 2010. 14