The purpose of this review is to discuss the pathophysiological pathways involved in pathogenesis of Alzheimers disease pointing out current and future pharmacological targets. Alzheimers disease is one of the most important neurodegenerative disorders in the developed world together with Parkinsons disease. Although this disease was described almost a century ago, the molecular mechanisms that lead to the development of the neuronal pathology are not clear at the moment. Furthermore, although enormous efforts have been done, an efficient treatment for the disease does not exist yet because the mechanism of neuronal cell death is unknown. In the present work we discuss, in depth, the potential mechanisms involved in apoptosis and neuronal death in Alzheimers disease. The biology, structure and physiological properties of β-amyloid peptide and related proteases (secretases) are discussed, as well as existing therapeutics and future strategies for the treatment of Alzheimer ’ s disease. Inhibition of production of amyloid peptides by secretase inhibitors has been suggested as one of the most rational and specific therapeutic approaches. Inhibition of apoptosis mediated by oxidative stress generation and mitochondrial alteration, or blockade of NMDA receptors could constitute suitable therapeutic strategies for Alzheimers disease. Finally, a multiple therapy with antioxidants, cell cycle inhibitors and other drugs modulating APP processing could be, in the future, a suitable strategy in order to delay Alzheimers disease progression.
Keywords: β-amyloid, secretases, presenilins, acetylcholine, neuronal cell death, apoptosis, cyclin-dependent kinases, glutamate receptors
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