Chapter 19: Targeted Protein Degradation as a Therapeutic Avenue for Alzheimer's Disease Check Access

Targeted protein degradation (TPD) is seriously considered in modern therapeutics for manipulating “undruggable” target proteins. However, TPD of extracellular proteins, which play essential roles in numerous diseases, is challenging. Recently, endosome targeting chimeras and lysosome targeting chimeras have been reported to internalize and degrade extracellular proteins. Conversely, no drug is available so far to treat Alzheimer's disease (AD). Abnormal deposition of extracellular Aβ aggregates and accumulation of intracellular Tau proteins are the principal cause of AD. Although a specific knockdown of Tau protein by proteolysis targeting chimeras (PROTACs) exists, no PROTAC is available to suppress extracellular Aβ yet. Inspired by the fact that the α-secretase mediated amyloid precursor protein processing prevents the generation of neurotoxic and pathogenic Aβ, a novel way of treating Aβ fibrillogenesis is outlined. A small engineered peptide conjugate, namely “artificial α-secretases” (ASs), selectively cleaved the disease-prone Aβ at various enzymatic cleavage sites, including that of α-secretases, to facilitate their excretion. Similarly, inspired by the serine proteases’ cleavage mechanism, the Asp-His-Ser triad containing miniature artificial proteases (mAPs) has been developed that degrades Aβ and its aggregates selectively. These innovative approaches may lead to new therapeutic options against AD.