Bio 362 Human Genetics Spring 2008
Alzheimer study sheet for April 8th
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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 (reminiscent of a previous week's topic)?
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.

Tanzi and Bertram, 2005:
What was odd about the early findings of linkage between AD and chromosome 21?
What genes are associated with early onset AD? Which genes represent the majority of cases?
What's the biochemical phenomenon that usually results from APP or presenilin mutations?
What are the names of the enzymes or enzyme complexes that cleave APP at different places?
What other aspects of amyloid metabolism (besides synthesis and aggregation) might be altered in the pathogenesis of Alzheimer disease?
How is cholesterol metabolism connected to Aβ metabolism?
What enzymes degrade Aβ ?
What are the different models for howAβ is toxic?

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? (Refer to this paper and the Tanzi and Bertram together.)

Lee et al., 2005 (questions from Chris and Katie to be emailed)

Figure 1 
1) What is BACE and what does it do to APP?
2) What are the three transgenic mouse lines shown in Figure 1? How do they differ? 
3) What are the seven different mouse lines shown in Figure 2? Which ones are monogenic and which are bigenic? 
Figure 2
4) In Figure 2B, how do increasing levels of BACE affect the amounts of full length APP vs. APP fragments? 
5) In Figure 2C, why does the C83 band decrease in intensity with more BACE, while C89 and C99 increase? 
Figure 3
6) What is the difference between Figures 3A, C and D?  
7) Would you say that high levels of BACE overexpression successfully rescue cells in the cortex? 
Figure 4 
8) What is the general correlation with BACE levels and amyloid formation in the cortex…the hippocampus?  
Extra credit: Why might low level increase in BASE lead to increased amyloid formation in the cortex and not the hippocampus? 
Figure 6 
9) What can we tell from figure 6 by comparing the 5685 immunoprecipitates to the PhAT immunoprecipitates?
Figure 7
10) Figure 7 illustrates how increased levels of BASE affect the timing of splicing of APP along the secretory pathway in the neuron. Where exactly in the neuron does APP get spliced in both the APP and APPxBASE-H mice strains, respectively?
Figure 8
11) Is APP making it to the sciatic nerve when exposed to higher levels of BACE?
12) Explain the authors' hypothesis for the paradoxical finding that increased BACE expression decreases A-beta deposition? (Look in introduction and Biochemical Markers… section) 

Jankowsky et al., 2005:
The experimental mice in this study were the result of two transgenic strains crossed together. What is in each transgenic strain, and why does crossing the two transgenes into one mouse lead to the desired effect?
See if you can figure out how the DNA was constructed to make one of the transgenic strains (see first section of materials and methods, and look up reference 15).
How does Figure 1 validate their setup? What different antibodies were used?
What different forms of Aβ are measured in each panel? Confirm that the amounts in the top three panels add up to the total in the bottom panel. Why is this a more direct confirmation of the expected phenomenon in the transgenic mouse, as opposed to the results in Figure 1?
What supporting data are in supplementary figures 2 and 3? Just look at the figure legends, which are included with the paper itself at the end.
Can amyloid lesions be prevented in the double transgenic mouse strain?
Now, on to the main experiment. What four cohorts were compared? Use Figure 3 to explain the setup.
How are figures 4A and 4C consistent? What implications do these data have for certain possible Alzheimer treatments?
In the quantifications of different forms of Aβ in the four cohorts as shown in Figure 5, what is are the signficant differences? What is seen here that can't be detected in the figure 4 data?
How do the four mouse cohorts differ in their brain cell pathology?
What behavioral oddities were documented? What do the experiments in Figure 7 say about what is causing the odd behavior?