L2 - AD and other neurodegenerative disorders

Question 0

Statistics on early versus late onset AD:

Answer 0

• early onset (65 years ) - ca. 94%

Question 1

Dementia and AD in the Netherlands stats:

Answer 1

• ca. 200 000 demented persons of which

- 130 000 diagnosed with AD (65%)

Question 2

Stats of early onset AD patients, …

Answer 2

• 54% - FAD (Familial AD)
• 40% - Sporadic
• 6% - Autosomal dominant forms

Question 3

Stats of late onset AD patients:

Answer 3

• 70% - sporadic
• 27% - familial AD
• 3% - autosomal dominant forms

Question 4

List AD neuropathologies:

Answer 4

• plaques
• tangles
• neuronal shrinkage and death
• gliosis (glial response to CNS damage - proliferation of astrocytes, microglia, and oligodendrocytes)
• loss of synapses

Question 5

AD genetic risk factors and the chromosomes they’re found on:

Answer 5

• APP (chr. 21)
• Presenilins
  
  • PSEN 1 (chr. 14)
  • PSEN 2 (chr. 1)
• ApoE polymorphism (chr. 19)

Question 6

Mutations on the various APP cleavage sites:

Answer 6

• beta-secretase (Swedish)
• alpha-secretase (Flemish, Dutch)
• gamma secretase (London, Florida)

Question 7

Non-genetic risk factors (act on the majority of AD cases)

Answer 7

• age; decrease in neuronal activity
• increased oxidative stress
• seeding
• epigenetics
• molecular misreading

Question 8

Explain a typical case of molecular misreading:

Answer 8

• dinucleotide deletions in simple monotonic base sequences of RNA; GAGAG, CTCT…
• if GA is removed, the resulting mutant protein is labelled a +1 protein
• APP +1 is an additional marker for early AD diagnosis in CSF

Question 9

Diseases which include UBB+1 accumulation

Answer 9

• down syndrome
• AD
• NOT Parkinson’s

Question 10

A dinucletide deletion in Ub mRNA results in…

Answer 10

• a frameshifted protein with 20 aa extra at the C-terminus