Atomic force microscopy to study molecular mechanisms of amyloid fibril formation and toxicity in Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by dementia and memory loss for which no cure or effective prevention is currently available. Neurodegeneration in AD is linked to formation of amyloid plaques found in brain tissues of Alzheimer's patients during post-mortem examination. Amyloid plaques are composed of amyloid fibrils and small oligomers - insoluble protein aggregates. Although amyloid plaques are found on the neuronal cell surfaces, the mechanism of amyloid toxicity is still not well understood. Currently, it is believed that the cytotoxicity is a result of the nonspecific interaction of small soluble amyloid oligomers (rather than longer fibrils) with the plasma membrane. In recent years, nanotechnology has contributed significantly to understanding the structure and function of lipid membranes and to the study of the molecular mechanisms of membrane-associated diseases. We review the current state of research, including applications of the latest nanotechnology approaches, on the interaction of lipid membranes with the amyloid-β (Aβ) peptide in relation to amyloid toxicity. We discuss the interactions of Aβ with model lipid membranes with a focus to demonstrate that composition, charge and phase of the lipid membrane, as well as lipid domains and rafts, affect the binding of Aβ to the membrane and contribute to toxicity. Understanding the role of the lipid membrane in AD at the nanoscale and molecular level will contribute to the understanding of the molecular mechanism of amyloid toxicity and may aid into the development of novel preventive strategies to combat AD.

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

“…On the other hand, data suggest that a moderate increase in membrane cholesterol content may be protective against AβO toxicity [38]. The extensive literature concerning Aβ-lipid membrane interactions and molecular level membrane modeling has recently been reviewed [32], including the possible involvement of metals in the mechanism [179]. …”

Dewetting transition assisted clearance of (NFGAILS) amyloid fibrils from cell membranes by graphene

“…In addition, modulating and interrupting the interaction between the cell membrane and peptide oligomers represents an alternative and important approach for the development of anti-PCD therapies. [28][29][30] Despite these great efforts, current commonly used antiPCDs agents, such as small drug molecules, 31, 32 polymers, 33 peptides, 34,35 and metal oxides 36 show only a moderate suppressive effect on the monomer fibrillization and a weak disassembling capability on the mature amyloid aggregations. It is thus an urgent task to explore and design novel approaches, including nanomaterial-based therapies, for PCDs.…”

“…NFGAILS peptide is the core fibrillization segment of human islet amyloid polypeptide (hIAPP [22][23][24][25][26][27][28], and is directly involved in type II diabetes mellitus. 5,6 Many experiments and simulations have demonstrated the similarities between the NFGAILS aggregation cytotoxicity in pancreatic β-islet cell with respect to its full length peptide.…”

CuII Binding to Various Forms of Amyloid‐β Peptides: Are They Friends or Foes?

“…[67] Furthermore, the morphology of the formed aggregates can be evaluated by means of microscopy (TEM or AFM). [49,68] Each of these techniques offers advantages but also suffers from drawbacks in terms of technique-related artifacts. [45] These drawbacks can be overcome by using multiple independent analytical techniques in parallel.…”