A beta deposition inhibitor screen using synthetic amyloid.
The formation, growth, and maturation of brain amyloid "senile" plaques are essential pathological processes in Alzheimer's disease (AD) and key targets for therapeutic intervention. The process of in vitro deposition of A beta at physiological concentrations onto plaques in AD brain preparations has been well characterized, but is cumbersome for drug discovery. We describe here a high-through put screen for inhibitors of A beta deposition onto a synthetic template (synthaloid) of fibrillar A beta immobilized in a polymer matrix. Synthaloid is indistinguishable from plaques in AD brain (the natural template) in deposition kinetics, pH profile, and structure-activity relationships for both A beta analogs and inhibitors. Synthaloid, in contrast to current A beta aggregation screens, accurately predicted inhibitor potency for A beta deposition onto AD cortex preparations, validating its use in searching for agents that can slow the progression of AD and exposing a previously inaccessible target for drug discovery.
Esler
W P
WP
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Stimson
E R
ER
Ghilardi
J R
JR
Felix
A M
AM
Lu
Y A
YA
Vinters
H V
HV
Mantyh
P W
PW
Maggio
J E
JE
D000682:Amyloid / Q000493:pharmacokinetics / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008567:Membranes, Artificial; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology
D000682:Amyloid; D016229:Amyloid beta-Peptides; D008567:Membranes, Artificial; D011994:Recombinant Proteins