The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs
Pp. 33-80 (48)
Luca Piemontese, Fulvio Loiodice, Sílvia Chaves and Maria Amelia Santos
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
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.
Alzheimer’s Disease, Aβ Amyloid Plaques, Acetylcholinesterase
Inhibitors, Disease-Modifying Agents, Donepezil, Innovative Targets, Insulin,
Multi-Functional Drugs, Multitarget Therapy, Neurodegenerative Disease,
Pioglitazone, PPARs, Type 2 Diabetes Mellitus, Type 3 Diabetes, Tacrine.
Dipartimento di Farmacia–Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Via E. Orabona 4, 70125 Bari, Italy.