BRM has developed proprietary rat strains which are translatable models for the characterization of type 1 and type 2 diabetes as well as immune-related diseases. Its technical competencies include design and conducting studies in autoimmunity (type 1 diabetes, lupus, Rheumatoid Arthritis and Multiple Sclerosis), metabolic disease (type 2 diabetes, metabolic syndrome, obesity, dyslipidemia, liver and kidney function), virology, neurodegenerative diseases, diabetic complications (retinopathy, neuropathy, nephropathy, and encephalopathy including Alzheimer’s disease) specialized animal model development and the production and care of multiple species.

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.
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