The invention provides methods for determining whether an agent preferentially inhibits Presenilin-1-comprised γ-secretase relative to Presenilin-2-comprised γ-secretase. The invention also provides agents that preferentially inhibit Presenilin-1-comprised γ-secretase relative to Presenilin-2-comprised γ-secretase, pharmaceutical compositions comprising such compounds, and methods of treating Alzheimer's disease using such compounds. The invention also discloses that the N-terminal domain of presenilin-1 and -2 determines the difference in the production of Aβ by PS1-comprised and PS2-comprised gamma secretases. This finding identified the structural determinant for the observed difference in the production of Aβ by PS1-comprised and PS2-comprised gamma secretases. Such structural determinant was not identified before. This invention also provides a method for determining whether an agent specifically binds the N terminus of PS1. The invention further provides for methods of treatment of Alzheimer's Disease by administration of an effective dose of an agent which specifically binds PS1, thereby inhibiting PS1 activity.
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