1. ALZHEIMER'S DISEASE (AD)
Senile dementia. Characterised by amyloid plaques + tau protein
~ 600,000 cases in UK
5% hereditary; 95% spontaneous
Frequent in Down's syndrome (extra chromosome 21)

2. AD - PLAQUES
From St George-Hyslop (2000)

3. PLAQUES
b-amyloid (bA)
peptide of aas; 42 aa peptide is most toxic
deposits as insoluble precipitate (b-sheets)
Nerves associated with plaques degenerate
Plaques also associated with 'tangles' of intracellular tau protein
bA precursor protein (bAPP) aas
membrane protein
Processed in 2 ways. One (a secretase) prevents bA formation; the other (b-secretase & g-secretase) facilitates it
gene on chromosome 21
hereditary AD - sometimes mutations in bAPP

4. PROCESSING OF bAPP
a-secretase
bAPP
b-secretase
+ g-secretase bA

5. b AMYLOID PRECURSOR PROTEIN (bAPP)
SEVKM
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA
TVIVITLVML
b-secretase
a-secretase
g-secretase SP
cysteine rich
acidic
KPI
OX2 Ab
lumen
cytosol
membrane N
Sites of mutations causing AD

6. INHERITED FORMS OF AD
May involve mutations in :
bAPP (rather rare)
presenilins (PS1 and PS2)
[50% of hereditary AD has mutations in PS1 or PS2]
PS1 and PS2
membrane proteins (>7 membrane spanning domains)
May be involved in signalling and/or apoptosis
Part of complex of proteins making up g-secretase

7. PRESENILIN 1 (PS1)
From Hardy (1997)

8. THE AMYLOID CASCADE HYPOTHESIS
(b-secretase)
From Mudher & Lovestone (2002)

9. WHY IS bA42 DAMAGING?
1. May disrupt Ca2+ regulation?
2. May damage mitochondria with liberation of oxygen free radicals
3. May initiate inflammatory response.
Alternatively: bA may have a significant normal physiological role (possibly as an inhibitor of synaptic transmission) and AD results from loss of this.

10. THE TAU AND TANGLE HYPOTHESIS
From Mudher & Lovestone (2002)

11. FACTORS THAT INCREASE LIKELIHOOD OF AD
bAPP mutations
PS-1/2 mutations
Unknown gene on chromosome 10
APOEe4
Head injury
Age
Aluminium ions??

12. POTENTIAL THERAPIES FOR AD
1. Acetylcholinesterase inhibitors
2. Drugs that inhibit b- and g-secretase
3. Immunization against bA
4. Cholesterol lowering drugs

13. b-SECRETASE - TARGET FOR THERAPY?
aspartic protease (homologous to pepsin) - membrane bound
3D structure known
mouse knockout - produces no bA; otherwise only slight behavioural effects
transgenics giving overproduction - increased bA
Peptide inhibitors available, but need small molecule inhibitors that can cross blood-brain barrier