Disorders%20with%20Complex%20Genetics

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Disorders with Complex Genetics
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Neuronal (Ab 42) Plaques in Alzheimers Disease
From http//www.rnw.nl/health/html/brain.html
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Neurofibrillary Tangles in Alzheimers Disease
From http//www.rnw.nl/health/html/brain.html
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Plaques and neurofibrillary tangles
From Department of Pathology, Virginia
Commonwealth University
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http//www.hosppract.com/genetics/9707gen.htm
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Following are from the NIA, Alzheimers
DiseaseEducation and Referral Center,
Alzheimers Disease Unraveling the Mystery
(www.niapublications.org/pubs/unraveling/01.htm
ff.)
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Amyloid precursor protein (APP) is membrane
protein that sits in the membrane and extends
outward. It is though tobe important for
neuronal growth, survival, and repair.
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Enzymes cut the APP into fragments, the most
important of which for AD is called b-amyloid
(beta-amyloid) orAb.
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Beta-amyloid is sticky so the fragments cling
together along with other material outside of the
cell, forming theplaques seen in the AD brain.
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Microtubules are like railroad tracks that
transport nutrition and other molecules.
Tau-proteins act as ties that stabilize the
structure of the microtubules. In AD, tau
proteins become tangled, unstabilizing the
structure of themicrotubule.
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Classification
(1) FAD v SAD Familial AD versus Sporadic AD

• No complete consensus
• Usually FAD at least 1 first degree relative
  affected
• Sometimes 2 second degree relatives

(2) Early v Late Onset

• Early onset (EOAD) usually before 65
• Early onset correlated with FAD
• LOAD late onset AD

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Breakthrough
(1) Downs Syndrome

• Have AD brain pathology in later life

(2) Pedigrees with dominant-like transmission

• Studied these first
• Concentrated on chromosome 21

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Alzheimers Disease, Type 1

• Several mutations in AAP gene on chromosome 21
• Most common Val717Iso
• Produce abnormal beta amyloid fragment
• 15-20 of early onset, familial AD
• Autosomal dominant

http//ghr.nlm.nih.gov/conditionalzheimerdisease
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http//perso.wanadoo.fr/alzheimer.lille/APP/APPmut
ations.html
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Alzheimers Disease, Type 3

• Mutations (gt 130) in the presenilin1 gene on
  chromosome 14
• Most mutations lead to amino acid substitution
• Overproduction of the beta amyloid fragment
• 30 - 70 of early onset, familial AD
• Autosomal dominant

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Alzheimers Disease, Type 4

• Mutations in the presenilin2 gene on chromosome
  1
• 2 alleles Asn141Iso and Met239Val
• Overproduction of the beta amyloid fragment
• lt 5 of early onset, familial AD (only a
  fewfamilies world wide)
• Autosomal dominant

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Alzheimers Disease, Type 2

• Epsilon 4 (e4, AKA E4) allele of the
  Apolipoprotein E (ApoE) gene on chromosome 19
  confers risk
• Epsilon 2 (e2, AKA E2) allele of the
  Apolipoprotein E geneon chromosome 19 confers
  protection
• Mechanism unclear ApoE is a very low density
  lipoprotein that transports cholesterol
• Most cases are late onset, familial
• Susceptibility Locus

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Prevalence of APOE genotypes in Alzheimers disease (AD) and controls. Prevalence of APOE genotypes in Alzheimers disease (AD) and controls. Prevalence of APOE genotypes in Alzheimers disease (AD) and controls.

Genotype Controls AD
E2/E2 1.3 0
E2/E3 12.5 3.4
E2/E4 4.9 4.3
E3/E3 59.9 38.2
E3/E4 20.7 41.2
E4/E4 0.7 12.9
Jarvik G, Larson EB, Goddard K, Schellenberg GD,
Wijsman EM (1996) Influence of apolipoprotein E
genotype on the transmission of Alzheimer disease
in a community-based sample. Am J Hum Genet
58191-200
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http//www.hosppract.com/genetics/9707gen.htm
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AD The Great Unknown What is causing the
majority of AD cases?

1. Unknown Mendelian forms (probably not)
2. Unknown major loci (probably not)
3. Phencopies
4. Multifactorial-threshold

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Current theory Multifactorial, involvingseveral
pathways.

• Protein accumulation ? placques tangles
• Inflammation Unregulated activation of glia
• Lipid distribution Lipid membrane site of APP
  cleavage.

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From Sleegers et al. (2010) Trends in Genetics,
26, 84-94, p. 87
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Nature Genetics 41, 1088 - 1093 (2009)
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HGSS Carey Figure 6.1
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Animal Models
Mice gratia http//www.kidscolorpages.com/mouse.ht
m
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Figure 1. Development of the Transgenic Mouse
Model of Alzheimer's Disease. The transgene
consists of the human APP gene containing a
mutation causing a rare form of early-onset
familial Alzheimer's disease (Val717Phe). The
transgene, whose expression is driven by the
platelet-derived growth factor (PDGF) promoter,
is microinjected into mouse eggs and implanted in
a pseudopregnant female mouse. After the progeny
are screened for the presence of the transgene,
they are bred and their offspring are analyzed
for pathologic features characteristic of
Alzheimer's disease. The brains of the transgenic
PDAPP (PDGF promoter expressing amyloid precursor
protein) mice have abundant  -amyloid deposits
(made up of the A   peptide), dystrophic
neurites, activated glia, and overall decreases
in synaptic density.
From NEJM Volume 3321512-1513
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From McGowan, Erikson Hutton (2006), Trend in
Genetics, 22 281-289.