Transcript Genetic Screening for Alzheimer`s Disease

Genetic Screening for
Alzheimer’s Disease
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 What is Alzheimer’s Disease (AD)?
Agenda
 Genes associated with AD
 The APOE gene
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 Type of dementia that causes problems with memory, thinking
and behavior
What is
Alzheimer’s
Disease (AD)?
 Most common form of dementia
 Not a normal part of aging
 Worsens over time
 Has no current cure, but treatments for symptoms are available
and research continues
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AD changes the
whole brain
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The prime
suspects for the
cause of cell
death and tissue
loss are plaques
and tangles
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Genes
associated
with AD
 Four leading genes determined to be causative elements: APP,
PS1, PS2 and APOE
 Mutations in APP, PS1 and PS2 cause early onset AD (younger than
65 years)
 APOE is a risk factor for late onset AD (older than 65 years)
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 Present in 30-50% of late onset AD patients
 Apolipoprotein E
The APOE
gene
 Secretory protein
 Synthesized in the liver
 Proposed function:
 Amyloid β aggregation and clearance
 Intracellular signaling through low-density lipoprotein receptorrelated protein (LRP)
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Screening and
Evaluation of
Deleterious
SNPs in the
APOE Gene of
AD
 SNP = Single-Nucleotide Polymorphism
 nsSNP = nonsynonymous SNP
 Several SNPs present in the APOE gene that serve as biomarkers
in exploring the genetic basis of AD
 Research Goal: Identify deleterious nsSNPs associated with the
APOE gene
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 SNPs are the most common polymorphisms of DNA sequence
variation for mapping complex genetic traits
 500,000 SNPs in coding regions of human genome
Why use SNPs,
specifically
nsSNPs?
 Several databases of SNPs
 nsSNPs cause changes in amino acid residues
 These mutations are most likely to cause structural changes
therefore altering the function of a protein (like APOE  plaques
and tangles)
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Used SNP detection
programs I-Mutant, Sort
Intolerant from Tolerant
(SIFT) and Polymorphism
Phenotype (PolyPhen) to
detect 88 SNPs on the
APOE gene of which 26
were nsSNPs and 5 were
deleterious
DDG value >-1.0 – least
stable
Tolerance index of 0.0 –
highly deleterious with
change in physiochemical
properties
PSIC score ≥2.0 – probably
damaging
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Used the Function
Analysis and Selection
Tool for Single
Nucleotide
Polymorphisms
(FASTSNP) server to
detect 7 nsSNPs with
high possible
functional effects
Risk score of 3-4: highly
polymorphic
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Used the Swiss Protein Data
Bank (PDB) viewer to
predict mutations in the
APOE gene and the Normal
Mode Analysis,
Deformation, and
Refinement (NOMAD-Ref)
server to detect 3 mutantstructures with higher total
energies and RMSD values
compared to the homology
modeled structure
Deviation in structure
implies a functional change
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Must test predicted impact of these nsSNPs using animal models or
cell lines to determine if the functionally of the protein has indeed
been altered
AD has a complex genetic background as well as environmental
factors, making research for a cure challenging
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