The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs

The treatment of neurodegenerative diseases is one of the most urgent challenges for pharmaceutical industry and public institutions. Alzheimer’s disease (AD), in particular, is a severe age-dependent dementia, currently affecting 44.4 million people worldwide, and this number is estimated to rise to 131.5 million in 2050. Only a few drugs are currently available for AD therapy, but these molecules are just able to temporarily improve the symptoms of the patients. Recently, important advancements have been achieved about the knowledge of this complex disease, even if, unfortunately, every attempt to obtain new efficient drugs for its therapy has failed. Following the theory of the multifactorial origin of the disease, in the last decade, researchers mainly focused on the development of multi-target agents, acting on the classical features recognized as important against the onset of AD, such as NMDA receptor antagonism, inhibition of cholinesterases (ChEs) and beta-Secretase (BACE), as well as inhibition of beta amyloid peptide (Aβ) aggregation and antioxidant activity. More recently, the modulation of dyshomeostasis of metal ions (i.e. copper, zinc and iron) in the AD patient brains, has been proposed as a disease-modifying therapeutic (DMT) strategy, due to their involvement in Aβ aggregation and in the formation of Reactive Oxygen Species (ROS). Noteworthy is the role of Peroxisome Proliferator-Activated Receptors (PPARs) in the onset of neurodegenerative diseases as well. PPARα expression levels have been reported to significantly decline in central nervous system (CNS) during the aging process. PPARγ, instead, is reported to have a neuroprotective effect, with a different mechanism that influences the Aβ precursor protein (APP) cleavage and the inflammatory response. The overexpression of certain types of ApoE also seems to increase the risk of developing AD. Therefore, the modulation of both PPAR subtypes seems to be a new interesting target to be explored. Other innovative targets as well are currently studied to find the final breakthrough for the therapy of AD: a number of years have passed since the approval of the last active drug in the treatment of this pathology and people now need a new hope.