Beyond the neurotransmitter-focused approach in treating Alzheimer's Disease: drugs targeting β-amyloid and tau protein
Francesco Panza1, Vincenzo Solfrizzi1, Vincenza Frisardi1, Bruno P. Imbimbo2, Cristiano Capurso3, Alessia D’Introno1, Anna M. Colacicco1, Davide Seripa4, Gianluigi Vendemiale3,4, Antonio Capurso1 and Alberto Pilotto5
1Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Bari, 2Research and Development Department, Chiesi Farmaceutici, Parma, 3Department of Geriatrics, University of Foggia, Foggia, 4Internal Medicine Unit, IRCCS Casa Sollievo dalla Sofferenza, San Giovanni Rotondo, Foggia, 5Geriatric Unit and Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

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 β-amyloid (Aβ), a 42-aminoacid peptide. Neurofibrillar tangles are composed of paired helical filaments of hyperphosphorylated tau protein. New, potentially disease-modifying, therapeutic approaches are targeting Aβ and tau protein. Drugs directed against Aβ include active and passive immunization, that have been found to accelerate Aβ clearance from the brain. The most developmentally advanced monoclonal antibody directly targeting Aβ is bapineuzumab, now being studied in a large Phase III clinical trial. Compounds that interfere with proteases regulating Aβ formation 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 particularly difficult due to inherent medicinal chemistry problems, and only one compound (CTS-21166) has reached clinical testing. Conversely, several compounds that inhibit γ-secretase, the pivotal enzyme that generates Aβ, have been identified, the most advanced being LY-450139 (semagacestat), now in Phase III clinical development. Compounds that stimulate α-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 Aβ 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. (Aging Clin Exp Res 2009; 21: 386-406) ©2009, Editrice Kurtis

[« Torna indietro] [Full text non abbonati] [Full text abbonati] [Acquista PDF]