The amyloid cascade hypothesis poses one possible explanation for the onset and progression of Alzheimer’s disease (AD). With this respect, neurotoxic effect is attributed to soluble and diffusive amyloid-β (Aβ) oligomers. Aβ peptides are produced by proteolytic cleavage of the hydrophobic transmembrane portion of the amyloid precursor protein (APP) by successive action of β- and γ-secretases. Aβ peptides are generated in several isoforms, out of which the most pronounced are Aβ40 and Aβ42 being the major constituents of amyloid plaques found in AD patients’ brains. Since the indisputable evidence pointed out to Aβ oligomers as toxic agents, several pathways to modulate or control the aggregation have been inspected. Given all these aspects, inhibitors of the β- and γ-secretases have gained the most attention. This chapter presents amyloid cascade hypothesis with current progress in the development of β- and γ-secretase modulators to counteract the Aβ burden.
Part of the book: Alzheimer's Disease
So far, the only clinically approved drugs that are effective in Alzheimer’s disease (AD) are those neurotransmitters oriented in their mode of action and focus, in particular, on the functional significance of acetylcholine or glutamate in the brain. Current AD drugs can, therefore, reduce the severity of cognitive symptoms, improve the quality of life, and stabilize the symptoms for some years, but they are not able to significantly modify the course of the disease. Complex disorders such as neurodegenerative diseases tend to result from multiple molecular abnormalities, not from a single defect. Moreover, a single target is unlikely to help in such cases because the cells can often find ways to compensate for a protein whose activity is affected by a drug. Thus, these limitations of the conventional “one-target, one-molecule” paradigm have triggered a recent shift in efforts to create drugs that hit more than one target simultaneously. The term multi-target-directed ligands (MTDLs) have been proposed to describe these hybrid molecules that are effective in treating complex diseases. Within our contribution, we would like to present general overview of MTDL design strategy in AD therapy, its positives and negatives, and finally summary of such multipotent compounds evaluated in clinical trials.
Part of the book: Neurodegenerative Diseases