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)

AD - PLAQUES

From St George-Hyslop (2000)

PLAQUES

-amyloid (A) peptide of 40-43 aas; 42 aa peptide is most toxicdeposits as insoluble precipitate (-sheets)

Nerves associated with plaques degenerate Plaques also associated with 'tangles' of intracellular tau protein

A precursor protein (APP) 770 aasmembrane proteinProcessed in 2 ways. One ( secretase) prevents A formation; the other (-secretase & -secretase) facilitates itgene on chromosome 21hereditary AD - sometimes mutations in APP

APP

-secretase

-secretase+ -secretase

A

PROCESSING OF APP

N

SEVKM DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA TVIVITLVML

-secretase -secretase -secretase

SP cysteine rich acidic KPI OX2 A

lumen cytosol

membrane

AMYLOID PRECURSOR PROTEIN (APP)

Sites of mutations causing AD

INHERITED FORMS OF AD

May involve mutations in :APP (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 apoptosisPart of complex of proteins making up -secretase

PRESENILIN 1 (PS1)

From Hardy (1997)

THE AMYLOID CASCADE HYPOTHESIS

-secretase)

From Mudher & Lovestone (2002)

WHY IS A42 DAMAGING?

1. May disrupt Ca2+ regulation?2. May damage mitochondria with liberation of

oxygen free radicals3. May initiate inflammatory response.

Alternatively: A may have a significant normal physiological role (possibly as an inhibitor of synaptic transmission) and AD results from loss of this.

THE TAU AND TANGLE HYPOTHESIS

From Mudher & Lovestone (2002)

FACTORS THAT INCREASE LIKELIHOOD OF AD

APP mutations

PS-1/2 mutations

Unknown gene on chromosome 10

APOEe4

Head injury

Age

Aluminium ions??

POTENTIAL THERAPIES FOR AD

1. Acetylcholinesterase inhibitors2. Drugs that inhibit - and -secretase3. Immunization against A4. Cholesterol lowering drugs

-SECRETASE - TARGET FOR THERAPY?

• aspartic protease (homologous to pepsin) - membrane bound

• 3D structure known

• mouse knockout - produces no A; otherwise only slight behavioural effects

• transgenics giving overproduction - increased A

• Peptide inhibitors available, but need small molecule inhibitors that can cross blood-brain barrier