Alzheimer's & Prions

Question 1

What is the pathophysiology of Alzheimer’s disease?

Answer 1

AB42 accumulates & oligomerizes in the brain. This affects synaptic efficiency. These oligamers create plaques –> inflamatory response –> oxidative injury –> tangles and widespread neuronal disfunction and loss, which manifests as dementia, which is when we see it in the clinic.

Question 2

How is AB42 made?

Answer 2

Amyoloid Precursor Protein (APP) from chomosome 21. If acted on by beta-secretase and then gamma-secretase, you get AB40 or 42 (depending on where g-sec cleaves)

Question 3

What causes non-genetic Alzheimer’s?

Answer 3

Failure of ApoE e4 to clear out amyloid

Question 4

What interventions would help alzheimer’s patients?

Answer 4

Decrease B-secretase (NOT GAMMA); Increase AB42 clearance or decrease its toxicity (prevent oligimerization); Decrease oxidation injury (chelate divalent metals); Decrease inflamatory response w/ NSAIDs, Decrease damage to synapses and neurons (memantine) or compensate for neuronal dysfunction (donepezil)

Question 5

What’s the difference between the normal prion and infectious prion protein?

Answer 5

Sequence is the same, but the abnormal folds differently and has more B-pleated sheets & different quaternary structure. The B-sheets are what make to stable & aggregatable

Question 6

What are the 3 ways to get prion disease?

Answer 6

Infection (<1%): prion is introduced through eating, surgery, or some other way (kuru, vCJD)
Inherited (10%): associated with a mutation in prion gene: familial CJD, GSS, FFI
Sporadic (90%): normal form sporadically forms abnormal form, converts others. CJD

Question 7

What’s the relationship between vCJD and BSE?

Answer 7

BSE can be transmitted to humans and cause vCJD, which is different that CJD.

Question 8

What is meant by different prion “strains”

Answer 8

Distinct isolates with characteristic features such as incubation time in defined host, clinical signs, distribution of protease resistant PrP in brain of affected animal. These features are stable on serial propagation. Certain biochemical properties of PrPSc appear to be strain-specific.

Question 9

What are the approximate PCR temps?

Answer 9

Melt DNA at 95, primers attach at 55, Taq Pol writes at 75. Use primer for disease allele to diagnose with PCR