Genes

Environment

Amyloid cascade hypothesis – the role of GSK3

AT8

GSK-3 inhibitor

GSK3

1. Hanger et al. Neurosci.Lett. 1992;147:58-62.2. Lovestone et al Curr Biol 1994;4(12):1077-86.3. Lovestone et al Biol.Psychiatry 1999;45(8):995-1003.

Animal models – GSK3 as the memory molecule

Mudher et al(2004) 9, 522530

Phen

otyp

e

GSK3 inhibited

Tet/GSK3

708090

100110120130140150160170

-30-20-10 0 10 20 30 40 50 60 70 80 90 100110120Time (mins)

Ampl

itude

EPS

P (%

bas

elin

e)

wt

Hooper et al Eur J Neurosci (2007); 25: 81-86.

GSK3 inhibitor

The GSK3 cascade and drug discovery for Alzheimer’s

• GSK3 inhibitors in phase IIb trials

• Drug discovery programme – DKK1 and the cascade

• Companion biomarkers

Dkk1 GSK3Dkk1