The invention provides methods for determining whether an agent piefeientiallyinhibits Presenilin-1-compiised .gamma.-secretase relative to Presenilin-2-comprised .gamma.-secretase. The invention also piovides agents thatpieferentially inhibit Presenilin-1-comprised y- secietase lelative toPresenilin-2-comprised .gamma.-sec.tau.etase, pharmaceutical compositionscompiising such compounds, and methods of heating Alzheimer's disease usingsuch compounds. The invention also discloses that the N-terminal domain ofpresenilis 1 and -2 determines the difference in the production of A.beta. byPS1-comprised and PS2-comprised gamma secretases. This finding identified thestructuial determinant for the observed difference in the production ofA.beta. by PS1-comprised and PS2-comprised gamma secretases. Such structuraldeteiminant was not identified before This invention also provides a methodfoi deteimining whether an agent specifically binds the N terminus of PS1 Theinvention further provides for methods of treatment of Alzheimer's Disease byadministration of an effective dose of an agent which specifically binds PSl,thereby inhibiting PS1 activity.
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