PROTAC Technology for the Treatment of Alzheimer’s Disease: Advances and Perspectives

Announcing a new review article publication for Acta Materia Medica journal. Although PROTAC technology is preferable to oligonucleotides and antibodies for the treatment of neurodegenerative diseases, many limitations, such as their pharmacokinetic properties, tissue distribution, and cell permeability, must be addressed. The authors of this article review recent advances in PROTAC technology, as well as PROTACs’ limitations, for the pharmaceutical targeting of aberrant proteins involved in AD and the therapeutic potential of dysregulated signaling, such as the PI3K/AKT/mTOR axis, for the management of AD.

Neurodegenerative diseases are characterized by the progression of neuronal degeneration, resulting in dysfunction of cognition and mobility. Many neurodegenerative diseases are due to proteinopathies arising from unusual protein accumulation and aggregation. The aggregation of misfolded proteins, such as β-amyloid, α-synuclein, tau, and polyglutamates, is a hallmark of Alzheimer’s disease (AD). These aggregated proteins are undruggable targets and usually do not respond to conventional small-molecule agents. Therefore, developing novel technologies and strategies for decreasing the levels of protein aggregates is critical for the treatment of AD. Recently, the emerging proteolysis targeting chimera (PROTAC) technology has been considered for artificial, selective degradation of aberrant target proteins. These engineered bifunctional molecules engage target proteins, which are then degraded either by the cellular degradation machinery via the ubiquitin-proteasome system or through the autophagylysosome degradation pathway.

Article Reference: Hiroyuki Inuzuka, Jing Liu and Wenyi Wei et al. PROTAC technology for the treatment of Alzheimer’s disease: advances and perspectives. Acta Materia Medica. Vol. 1(1). DOI: 10.15212/AMM-2021-0001

Keywords: PROTAC, ubiquitin-proteasome system, protein degradation, autophagy, Alzheimer’s disease

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