Extracellular Amyloid β-protein (1–42) Oligomers Anchor Brain Cells and Make them inert as an Unconventional Integrin-Coupled Ligand

Different Extracellular β-Amyloid (1-42) Aggregates Differentially Impair Neural Cell Adhesion and Neurite Outgrowth through Differential Induction of Scaffold Palladin

“…The distribution of intracellular palladin in SH-SY5Y/HT22 cells was analyzed by immunofluorescence (IF) microscopy as described previously [ 29 ], with slight modification. For palladin IF staining, the cells were incubated with AF488-conjugated anti-palladin antibody (green) (sc166563 AF488, Santa Cruz, Shanghai, China) at 4 °C overnight.…”

Conformational Essentials Responsible for Neurotoxicity of Aβ42 Aggregates Revealed by Antibodies against Oligomeric Aβ42

“…According to the information reflected by the anti-Aβ42 antibodies involved in either active (i.e., immunization with Aβ42 or its fragments) or passive immunization (i.e., parenteral administration of anti-Aβ antibodies), the most likely implication of Aβ42O toxicity is that Aβ42Os act as alternative ligands or membrane-bound proteins, disrupting or destroying some normal signaling and membrane structures of neural cells, especially synaptic sites, as previously reported [ 75 ]. Thus, an alternative ligand mechanism for Aβ42O is proposed [ 24 ]. The metastability and heterogeneity of Aβ42Os make their mechanisms diverse and complex.…”

“…On the other hand, it is difficult for larger Aβ42 aggregates to approach neural cell membranes or receptors, but at the same time they are easily deposited in the matrix outside neural cells. The seeding of Aβ42 aggregates (either soluble or deposited form) to the extracellular space is likely to affect the interactions between cells and acellular components in the extracellular matrix (ECM) or between cells, gradually anchors neural cells and makes them become inert, eventually leading to neural cell damage and loss [ 24 ]. The recent report [ 24 ] also proposes that extracellular Aβ42 aggregates exert detrimental anchoring effects on neural cells, which are significantly attenuated by the application of anti-oligomeric Aβ42 scFv antibodies.…”

“…According to a recent report [ 24 ], extracellular Aβ42 aggregates (either in soluble/suspended or deposited/attached forms) act as extracellular tethering matrices for neural cells through their anchoring effects on neural cells, thereby gradually tethering the neural cells. It can be speculated that to break free from the “shackles” of extracellular Aβ42 aggregates, neural cells are bound to undergo cascading changes, such as changes in intracellular regulatory substances (in terms of both expression levels and subcellular distribution) or cell behavior (e.g., migration and adhesion) or morphogenesis.…”

“…An increasing number of studies have demonstrated that in addition to directly destroying the integrity and permeability of neuronal cell membranes by forming membrane pores [ 12 , 13 , 14 ], extracellular Aβ42Os are mainly capable of binding to a variety of membrane receptors or membrane proteins on the surface of neural cells in a ligand-like manner, resulting in synaptic dysfunction and neurodegeneration through multiple abnormal alterations in the corresponding signaling pathways [ 5 , 14 , 15 ]. More than 20 putative receptors or membrane proteins have been reported to be associated with the neurotoxic activity of AβO oligomers, including the N-methyl-d-aspartate receptor [ 16 , 17 , 18 ], p75 neurotrophin receptor [ 19 , 20 ], prion-like protein [ 21 , 22 ], α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor [ 18 , 23 ], and integrin receptors [ 24 ]. Notably, all these receptors or membrane proteins are often multi-subunit complexes.…”