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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 b -amyloid ( b A)
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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 b-amyloid (bA) peptide of 40-43 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) 770 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
PROCESSING OF bAPP a-secretase bAPP b-secretase + g-secretase bA
membrane lumen cytosol SP cysteine rich acidic KPI OX2 Ab TVIVITLVML SEVKM DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA b-secretase a-secretase g-secretase b AMYLOID PRECURSOR PROTEIN (bAPP) N Sites of mutations causing AD
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
PRESENILIN 1 (PS1) From Hardy (1997)
THE AMYLOID CASCADE HYPOTHESIS (b-secretase) From Mudher & Lovestone (2002)
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.
THE TAU AND TANGLE HYPOTHESIS From Mudher & Lovestone (2002)
FACTORS THAT INCREASE LIKELIHOOD OF AD • bAPP mutations • PS-1/2 mutations • Unknown gene on chromosome 10 • APOEe4 • Head injury • Age • Aluminium ions??
POTENTIAL THERAPIES FOR AD 1. Acetylcholinesterase inhibitors 2. Drugs that inhibit b- and g-secretase 3. Immunization against bA 4. Cholesterol lowering drugs
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