Editors' Showcase 2021/2022: Insights in Cell Adhesion and Migration

Editorial

12 June 2023

Editorial: Editors’ showcase 2021/2022: insights in cell adhesion and migration

Claudia Tanja Mierke

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Editors

Akihiko Ito

Faculty of Medicine, Kindai University

Claudia Tanja Mierke

Leipzig University

Impact

Review

26 July 2022

Amyloid precursor protein (APP) and amyloid β (Aβ) interact with cell adhesion molecules: Implications in Alzheimer’s disease and normal physiology

Grant Pfundstein

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Vladimir Sytnyk

APP structure and processing. (A) APP is composed of a large N-terminal extracellular domain, transmembrane region, and short cytoplasmic tail. The extracellular domain comprises two rigidly folded regions, E1 and E2, joined by an acidic domain (AcD). E1 contains a heparin-binding domain (HBD) within a larger growth factor-like domain (GFLD), and a copper/zinc-binding domain (CuBD). E2 comprises the second HBD and CuBD. The juxtamembrane region contains the α- and β-cleavage sites, while the γ-cleavage site is located within the transmembrane domain. The C-terminal intracellular domain (AICD) contains the YENPTY sequence, which binds cytosolic adaptor proteins. (B) APP is primarily processed along two opposing pathways. In amyloidogenic processing, APP is cleaved by β-secretase (BACE1) at the N-terminus of Aβ, generating sAPPβ and the membrane-bound β-CTF. Subsequent γ-secretase cleavage of β-CTF releases the Aβ peptide into the extracellular/lumenal space and AICD into the cytosol. Aβ peptides aggregate and form oligomers (AβO). In non-amyloidogenic processing, APP is cleaved by α-secretase (ADAM10) within the Aβ region, producing sAPPα and α-CTF. Ensuing cleavage of α-CTF by γ-secretase liberates P3 into the extracellular/lumenal space and AICD into the cytosol.

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder in which dysfunction and loss of synapses and neurons lead to cognitive impairment and death. Accumulation and aggregation of neurotoxic amyloid-β (Aβ) peptides generated via amyloidogenic processing of amyloid precursor protein (APP) is considered to play a central role in the disease etiology. APP interacts with cell adhesion molecules, which influence the normal physiological functions of APP, its amyloidogenic and non-amyloidogenic processing, and formation of Aβ aggregates. These cell surface glycoproteins also mediate attachment of Aβ to the neuronal cell surface and induce intracellular signaling contributing to Aβ toxicity. In this review, we discuss the current knowledge surrounding the interactions of cell adhesion molecules with APP and Aβ and analyze the evidence of the critical role these proteins play in regulating the processing and physiological function of APP as well as Aβ toxicity. This is a necessary piece of the complex AD puzzle, which we should understand in order to develop safe and effective therapeutic interventions for AD.

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