From the multifactorial nature of Alzheimer`s disease to multitarget therapy: the contribution of the translational approach.
The drug discovery for disease-modifying agents in Alzheimer disease (AD) is facing a failure of clinical trials with drugs based on two driving hypotheses, i.e. the cholinergic and amyloidogenic hypotheses. In this article we recapitulate the main aspects of AD pathology, focusing on possible mechanisms for synaptic dysfunction, neurodegeneration and inflammation. We then present the pharmacological and neurobiological profile of a novel compound (CHF5074) showing both anti-inflammatory and gamma-secretase modulatory activities, discussing the possible time-window for effective treatment in an AD transgenic mouse model. Finally, the concept of cognitive reserve is introduced as possible target for preventive therapies.
Health Science and Technologies Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara di Sopra 41/E, 40064 Ozzano Emilia, Bologna, Italy. laura.calza@unibo.it
Laura
L
Calzà
Vito Antonio
VA
Baldassarro
Alessandro
A
Giuliani
Luca
L
Lorenzini
Mercedes
M
Fernandez
Chiara
C
Mangano
Sandra
S
Sivilia
Marco
M
Alessandri
Marco
M
Gusciglio
Roberta
R
Torricella
Luciana
L
Giardino
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000627:therapeutic use; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D051379:Mice; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D013569:Synapses / Q000187:drug effects / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects; D057170:Translational Research, Biomedical
C522246:1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; D000893:Anti-Inflammatory Agents; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D018697:Nootropic Agents; D005480:Flurbiprofen; D053829:Amyloid Precursor Protein Secretases