title: Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease.
abstract: The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT(+)). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.
authors.affiliation: Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy; Department of Clinical Research in Neurology, University of Bari Aldo Moro, "Pia Fondazione Cardinale G. Panico", Tricase, Lecce, Italy; Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy.
authors.forename: Francesco
authors.identifier: 0000-0002-7220-0656
authors.initials: F
authors.lastname: Panza
authors.affiliation: Geriatric Medicine-Memory Unit and Rare Disease Centre, University of Bari Aldo Moro, Bari, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Solfrizzi
authors.affiliation: Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy.
authors.forename: Davide
authors.identifier: 0000-0001-7331-0470
authors.initials: D
authors.lastname: Seripa
authors.affiliation: Research & Development Department, Chiesi Farmaceutici, Parma, Italy.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
authors.affiliation: Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy; Psychiatric Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: Madia
authors.initials: M
authors.lastname: Lozupone
authors.affiliation: Physical Medicine and Rehabilitation Section, "OORR" Hospital, University of Foggia, Foggia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Santamato
authors.affiliation: Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy; Department of Clinical Research in Neurology, University of Bari Aldo Moro, "Pia Fondazione Cardinale G. Panico", Tricase, Lecce, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zecca
authors.affiliation: Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy; Department of Clinical Research in Neurology, University of Bari Aldo Moro, "Pia Fondazione Cardinale G. Panico", Tricase, Lecce, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Barulli
authors.affiliation: Psychiatric Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Bellomo
authors.affiliation: Department of Orthogeriatrics, Rehabilitation and Stabilization, Frailty Area, E.O. Galliera NR-HS Hospital, Genova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Pilotto
authors.affiliation: Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Daniele
authors.affiliation: Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Greco
authors.affiliation: Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy; Department of Clinical Research in Neurology, University of Bari Aldo Moro, "Pia Fondazione Cardinale G. Panico", Tricase, Lecce, Italy.
authors.forename: Giancarlo
authors.identifier: 0000-0003-0423-3242
authors.initials: G
authors.lastname: Logroscino
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019317:Evidence-Based Medicine; D006801:Humans; D008751:Methylene Blue / Q000008:administration & dosage*; D058990:Molecular Targeted Therapy / Q000379:methods*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D016896:Treatment Outcome; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D016875:tau Proteins; D008751:Methylene Blue