Beyond the neurotransmitter-focused approach in treating Alzheimer's Disease: drugs targeting β-amyloid and tau protein Aging Clinical and Experimental Research

Drugs currently used to treat Alzheimer's Disease (AD) have limited therapeutic value and do not affect the main neuropathological hallmarks of the dis- ease, i.e., senile plaques and neurofibrillar tangles. Senile plaques are mainly formed of β-amyloid (Aβ), a 42-aminoacid peptide. Neurofibrillar tangles are composed of paired helical filaments of hyperphos- phorylated tau protein. New, potentially disease-mod- ifying, therapeutic approaches are targeting Aβand tau protein. Drugs directed against Aβinclude active and passive immunization, that have been found to accel- erate Aβ clearance from the brain. The most devel- opmentally advanced monoclonal antibody directly targeting Aβis bapineuzumab, now being studied in a large Phase III clinical trial. Compounds that interfere with proteases regulating Aβformation from amyloid precursor protein (APP) are also actively pursued. The discovery of inhibitors of β-secretase, the enzyme that regulates the first step of the amyloidogenic metabolism of APP, has been revealed to be particu- larly difficult due to inherent medicinal chemistry problems, and only one compound (CTS-21166) has reached clinical testing. Conversely, several com- pounds that inhibit γ -secretase, the pivotal enzyme