Title:The Multifactorial Nature of Alzheimer's Disease for Developing Potential Therapeutics
Volume: 13
Issue: 15
Author(s): M. Carmo Carreiras, Eduarda Mendes, M. Jesus Perry, Ana Paula Francisco and J. Marco-Contelles
Affiliation:
Keywords:
Aβ, Alzheimer's disease, Ca2+ dishomeostasis, ChEs, Dual AChE/BuChE inhibitors, MAO, metal chelators, oxidative
stress.
Abstract: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with several target proteins contributing
to its aetiology. Pathological, genetic, biochemical, and modeling studies all point to a critical role of Aβ aggregation
in AD. Though there are still many enigmatic aspects of the Aβ cascade, none of the gaps invalidate the hypothesis. The
amyloid hypothesis determines that the production, aggregation and accumulation of Aβ in the brain gives rise to a cascade
of neurotoxic events that proceed to neuronal degeneration. Different targets of the disease include APP pathogenic
cleavage, cytoskeletal destabilization, neurotransmitter and ion dyshomeostasis, metal ion accumulation, protein misfolding,
oxidative stress, neuronal death and gene mutations. Thus, disease-modifying treatments for AD must interfere with
the pathogenic steps responsible for the clinical symptoms: the deposition of extracellular Aβ plaques, the intracellular
neurofibrillary tangles, inflammation, oxidative stress, iron deregulation, among others.
The observations supporting the development of multifunctional compounds in association with the perception that several
dual binding site AChEIs were able to reach different targets guided the development of a new drug design strategy,
the multi-target-directed-ligand (MTDL) approach. This may be regarded as the buildup of hybrid molecules composed of
distinct pharmacophores of different drugs. Thus, each pharmacophore of the new hybrid drug would preserve the capacity
of interacting with their specific sites on the targets and, therefore, generate multiple specific pharmacological responses
which would enable the treatment of multi-factorial diseases. This review summarizes a few current therapeutic
trends on MTDL strategy intended to halt or revert the progression of the disease.
