Bio 363 Human Genetics Spring 2013
Alzheimer study sheet
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Background, including Decoding Darkness :
What are the two main subcellular symptoms of Alzheimer disease? What are these features made of?
Originally what were the two different hypotheses for the pathway of causation of these symptoms? Which seems to be true? Within that pathway, what controversy still exists?
In what different ways can APP be metabolized? Which way is pathogenic?
Come to class ready to discuss your perceptions and responses to Decoding Darkness.
Bertram et al, 2010:
Contrast early and late onset AD.
What genes are associated with early onset AD? What are the molecular mechanisms?
What is the role of ApoE in late onset AD?
Have other genes been identified through a candidate approach?
What is a genome wide association study (GWAS)?
Of the possible AD-associated genes identified via GWAS, are there any compelling ones?
What is the deal with the "missing heritability" of AD?
Where is AD research headed next?
Hardy and Selkoe, 2002:
What evidence argued against the tau hypothesis?
What different physical forms of Aβ can exist, and what's the evidence for which form is pathogenic?
What are some possible therapeutic approaches?
Jiang et al., 2008
Figures 1 through 5 all involve the same sort of setup to assess Aβ 42 uptake and breakdown by microglia. What are microglia? What are the general logistics for these assays? What are the different ways in which Aβ 42 is tracked?
Fig 1: What intracellular enzyme is demonstrated to be involved in Aβ 42 breakdown, and how is this shown?
Fig 2: What additional component is added in to assess the effect on Aβ breakdown?
Fig 3: How do these conditions mimic in a different way what was done in Fig 2? What does the chemical GW3965 activate?
Fig 4: How are cells from mutant strains used to show the opposite effect of results from Figs 2 and 3?
Fig 5: How are cells from a different mutant strain used to show the method through which the GW3965 must have been working?
Fig 6: Now we're extracellular. What are astrocytes, and what is conditioned medium? Note that insulin is a competitive inhibitor for Aβ breakdown by IDE. What conditions are required for IDE to be able to break down extracellular Aβ?
In the discussion, at the end of p. 687, the authors mention that recent evidence downplays one sort of Aβ metabolism which had been emphasized in the Tanzi review paper. How is most Aβ removed? Fig 9 gives a good summary.
What treatments are tried on a mouse Alzheimers model as a result of the earlier data in this paper? Are the results promising?
Beck et al., 2004
What was odd about the phenotypes of the affected people in the family studied?
Figs 3 & 4: What result suggested mosaicism in the mother?
How can mosaicism make DNA testing for disease tricky?
Fig 5: Allele specific PCR used primers specific for both the locus in question as well as a nearby SNP. Most people will show a band with two (or one if homozygous) out of the four possible primer pairs. How did the results confirm the mother's and children's genotypes?