Abstract
Neurodegenerative diseases (NDs) are characteristic with progression of neuron degeneration, resulting in dysfunction of cognition and mobility. Many neurodegenerative diseases are because of proteinopathies that results from unusual protein accumulations and aggregations. The aggregation of misfolded proteins like β-amyloid, α-synuclein, tau, and polyglutamates are hallmarked in Alzheimer's disease (AD), which are undruggable targets, and usually do not respond to conventional small-molecule agents. Therefore, developing novel technology and strategy for reducing the levels of protein aggregates would be critical for treatment of AD. Recently, the emerging proteolysis targeting chimeras (PRPTACs) technology has been significantly considered for artificial and selective degradation of aberrant target proteins. These engineered bifunctional molecules engage target proteins to be degraded by either the cellular degradation machinery in the ubiquitin-proteasome system (UPS) or via the autophagy-lysosome degradation pathway. Although the application of PROTACs technology is preferable than oligonucleotide and antibodies for treatment of NDs, many limitations such as their pharmacokinetic properties, tissue distribution and cell permeabilities, still need to be corrected. Herein, we review the recent advances in PROTACs technology with their limitation for pharmaceutical targeting of aberrant proteins involved in Alzheimer's diseases. We also review therapeutic potential of dysregulated signaling such as PI3K/AKT/mTOR axis for the management of AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the leading cause of dementia in older people and the sixth leading cause of death [1]
Several methods based on chemically mediated targeted protein degradation have been established, including hydrophobic tagging, molecular glues, autophagy-targeting chimeras, autophagosome-tethering compounds (ATTECs), lysosome-targeting chimeras (LYTACs), and proteolysis targeting chimera (PROTAC) (Figure 3)
We discuss AD-specific PROTACs and several others that have been used for targeting aberrant proteins/signaling pathways that are dysregulated in the tumor microenvironment
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the leading cause of dementia in older people and the sixth leading cause of death [1]. Senile plaques are usually caused by the aberrant deposition of aggregated protein fragments called β-amyloid (Aβ; Aβ42 and Aβ40) among nerve cells [5] In this event, called amyloidosis of the brain, Aβ peptides are cleaved from the amyloid precursor protein (APP) and aggregate as soluble toxic oligomeric Aβ. The aggregation of these soluble toxic oligomers results in the creation of hydrophobic surfaces; subsequently, insoluble fibrils are formed for disruption of the phospholipid bilayer [6], which is considered the main underlying cause of AD [7]. The mechanistic principle underlying the formation of both senile plaques and NFT has been well established and is considered a key hallmark of AD [10, 11] (Figure 1)
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