The present invention provides methods and compositions for modulating levels of amyloid-β peptide (Aβ) exhibited by cells or tissues. The invention also provides pharmaceutical compositions and methods of screening for compounds that modulate Aβ levels. The invention also provides modulation of Aβ levels via selective modulation (e.g., inhibition) of ATP-dependent γ-secretase activity. The invention also provides methods of preventing, treating or ameliorating the symptoms of a disorder, including but not limited to an Aβ-related disorder, by administering a modulator of γ-secretase, including, but not limited to, a selective inhibitor of ATP-dependent γ-secretase activity or an agent that decreases the formation of active (or optimally active) γ-secretase. The invention also provides the use of inhibitors of ATP-dependent γ-secretase activity to prevent, treat or ameliorate the symptoms of Alzheimers disease.
