Drugs currently used to treat
Alzheimer's Disease (AD) have limited therapeutic value and do not affect the main neuropathological hallmarks of the disease, i.e.,
senile plaques and neurofibrillar tangles.
Senile plaques are mainly formed of
beta-amyloid (Abeta), a 42-aminoacid
peptide. Neurofibrillar tangles are composed of paired helical filaments of hyperphosphorylated
tau protein. New, potentially disease-modifying, therapeutic approaches are targeting Abeta and
tau protein. Drugs directed against Abeta include active and passive immunization, that have been found to accelerate Abeta clearance from the brain. The most developmentally advanced
monoclonal antibody directly targeting Abeta is
bapineuzumab, now being studied in a large Phase III clinical trial. Compounds that interfere with
proteases regulating Abeta formation from
amyloid precursor
protein (APP) are also actively pursued. The discovery of inhibitors of
beta-secretase, the
enzyme that regulates the first step of the amyloidogenic metabolism of APP, has been revealed to be particularly difficult due to inherent medicinal chemistry problems, and only one compound (CTS-21166) has reached clinical testing. Conversely, several compounds that inhibit
gamma-secretase, the pivotal
enzyme that generates Abeta, have been identified, the most advanced being LY-450139 (
semagacestat), now in Phase III clinical development. Compounds that stimulate
alpha-secretase, the
enzyme responsible for the non-amyloidogenic metabolism of APP, are also being developed, and one of them, EHT-0202, has recently entered Phase II testing. Potent inhibitors of Abeta aggregation have also been identified, and one of such compounds, PBT-2, has provided encouraging neuropsychological results in a recently completed Phase II study. Therapeutic approaches directed against
tau protein include inhibitors of
glycogen synthase kinase- 3 (GSK-3), the
enzyme responsible for tau phosphorylation and
tau protein aggregation inhibitors. NP-12, a promising
GSK-3 inhibitor, is being tested in a Phase II study, and
methylthioninium chloride, a
tau protein aggregation inhibitor, has given initial encouraging results in a 50-week study. With all these approaches on their way, the hope for disease-modifying
therapy in this devastating disease may become a reality in the next 5 years.