Physiology and pharmacology of amyloid precursor protein

Yoonsuk Cho; Han-Gyu Bae; Eitan Okun; Thiruma V Arumugam; Dong-Gyu Jo

doi:10.1016/j.pharmthera.2022.108122

Physiology and pharmacology of amyloid precursor protein

Pharmacol Ther. 2022 Jul:235:108122. doi: 10.1016/j.pharmthera.2022.108122. Epub 2022 Feb 1.

Authors

Yoonsuk Cho¹, Han-Gyu Bae¹, Eitan Okun², Thiruma V Arumugam³, Dong-Gyu Jo⁴

Affiliations

¹ School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea.
² The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan 5290002, Israel; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel; The Pauld Feder Laboratory on Alzheimer's Disease Research, Israel.
³ School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea; School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia. Electronic address: g.arumugam@latrobe.edu.au.
⁴ School of Pharmacy, Sungkyunkwan University, Suwon 16419, South Korea; Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul 06351, South Korea; Biomedical Institute for Convergence, Sungkyunkwan University, Suwon 16419, South Korea. Electronic address: jodg@skku.edu.

PMID: 35114285
DOI: 10.1016/j.pharmthera.2022.108122

Abstract

Amyloid precursor protein (APP) is an evolutionarily conserved transmembrane protein and a well-characterized precursor protein of amyloid-beta (Aβ) peptides, which accumulate in the brains of individuals with Alzheimer's disease (AD)-related pathologies. Aβ has been extensively investigated since the amyloid hypothesis in AD was proposed. Besides Aβ, previous studies on APP and its proteolytic cleavage products have suggested their diverse pathological and physiological functions. However, their roles still have not been thoroughly understood. In this review, we extensively discuss the evolutionarily-conserved biology of APP, including its structure and processing pathway, as well as recent findings on the physiological roles of APP and its fragments in the central nervous system and peripheral nervous system. We have also elaborated upon the current status of APP-targeted therapeutic approaches for AD treatment by discussing inhibitors of several proteases participating in APP processing, including α-, β-, and γ-secretases. Finally, we have highlighted the future perspectives pertaining to further research and the potential clinical role of APP.

Keywords: APP intracellular domain; Alzheimer’s disease; Amyloid precursor protein; Soluble APPα.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Amyloid
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor* / chemistry
Amyloid beta-Protein Precursor* / metabolism
Humans

Substances

Amyloid
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Amyloid Precursor Protein Secretases