Use of Transgenic Animals in study of Neurological Disorders

1. INDIAN INSTITUTE OF TECHNOLOGY ROORKEE
Use of Transgenic Animals in study of Neurological Disorders
Submitted by Sourik Dey (18610023), M.Sc Biotechnology, 1st Year, 2018-2019
Transgenic Animal Technology (BTN-631)
Submitted to
Dr Partha Roy

2. 2
NEURODEGENERATIVE DISEASE MODELS
• The neurodegenerative disease models that I will
discuss are as follows:-
1. ALZHEIMER’S DISEASE MODEL
2. HUNTINGTON’S DISEASE MODEL

3. 3
• Alzheimer's disease - It is a
chronic neurodegenerative disease that usually
starts slowly and gradually worsens over time
causing dementia.
• The amyloid hypothesis postulates that
extracellular amyloid beta (Aβ) deposits are the
fundamental cause of the disease.
• Amyloid plaques – amyloid beta peptide (Aβ),
fragment of β-amyloid precursor protein (APP).
• The mutations in the APP gene makes it prone to
cleavage by proteases thus leading to amyloid beta
proteins that get deposited in the brain as senile
plaques.
Alzheimer’s Disease

4. 4
• Pedigree analysis of autosomal dominant AD
identified a mutation (V717F) in
the APP gene.
• Using the APP V717F mutation, the first
transgenic mouse model of AD (PDAPP) was
developed approach using a platelet derived
growth factor-β (PDGF) promoter.
• The PDGF promoter was chosen as it was
highly expressed in the CNS. It drove strong
expression of exogenous transgenes in
neurons.
• The PDAPP mouse exhibited plaque
pathology by 6–9 months of age but did not
show NFT pathology or substantial cell loss.
AD MOUSE MODEL DESIGNING

5. 5
• Tau protein is the major microtubule
associated protein (MAP) of a mature
neuron. They interact with tubulin and
promote their assembly into microtubules
and stabilize the microtubule network.
• The microtubule assembly promoting
activity of tau, a phosphoprotein, is
regulated by its degree of phosphorylation.
Normal adult human brain tau contains 2–3
moles phosphate/mole of tau protein.
• Hyperphosphorylation of tau depresses this
biological activity of tau as it gets
polymerized into paired helical filaments
(PHF) admixed with straight filaments (SF)
forming neurofibrillary tangles in AD
model.

6. 6
Different Mouse Models designed with different mutations to study the
disease progression at various stages of development.

7. 7
Huntington’s Disease
• Huntington's disease - Caused by an
inherited defect in a single gene and is an
autosomal dominant disorder.
• Mutations in the HTT gene
cause Huntington disease which codes for
a protein called huntingtin.
• The HTT mutation that causes Huntington
disease involves a DNA segment known as
a CAG trinucleotide repeat.
• Normally, the CAG segment is repeated 10
to 35 times within the gene.
• In people with Huntington disease, the
CAG segment is repeated 36 to more than
120 times.

8. 8
Why mouse modelling?
• High degree of shared complexity between mouse and humans makes mouse models especially useful (NCBI
2005)
• HTT mutation has been determined as the single cause of the disease. Therefore, it should be easier to generate an
accurate mouse model of HD than for other conditions with multiple, often unknown causes.
• There is more refined technology to carry this out (NCBI 2005)
• Model is relatively inexpensive to maintain, easy to ship, have short generation times and produce large numbers
of offspring.

9. 9
• Researchers have focused on animal
models that closely mimic various
aspects of the disease.
• The most popular models are the
transgenic rodent models, in
particular the R6/2 mouse;
approximately 50% of all
polyglutamine disease research are
conducted with this particular strain.
• R6/2 express the N-terminal
fragment of Htts first exon and
display some of the progressive
behavioral/pathological defects
associated with the disease within 2-
3 months of birth.

10. 10

11. 11
ACKNOWLEDGEMENT
I would like to thank Dr. Partha Roy for his
constant guide and support throughout the
entire coursework.

12. 12
Thank You