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      Atomic force microscopy for single molecule characterisation of protein aggregation

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          Abstract

          The development of atomic force microscopy (AFM) has opened up a wide range of novel opportunities in nanoscience and new modalities of observation in complex biological systems. AFM imaging has been widely employed to resolve the complex and heterogeneous conformational states involved in protein aggregation at the single molecule scale and shed light onto the molecular basis of a variety of human pathologies, including neurodegenerative disorders. The study of individual macromolecules at nanoscale, however, remains challenging, especially when fully quantitative information is required. In this review, we first discuss the principles of AFM with a special emphasis on the fundamental factors defining its sensitivity and accuracy. We then review the fundamental parameters and approaches to work at the limit of AFM resolution in order to perform single molecule statistical analysis of biomolecules and nanoscale protein aggregates. This single molecule statistical approach has proved to be powerful to unravel the molecular and hierarchical assembly of the misfolded species present transiently during protein aggregation, to visualise their dynamics at the nanoscale, as well to study the structural properties of amyloid-inspired functional nanomaterials.

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          Most cited references 185

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          Protein misfolding, functional amyloid, and human disease.

          Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior.
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            The amyloid hypothesis of Alzheimer's disease at 25 years

            Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
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              Principles that govern the folding of protein chains.

               C ANFINSEN (1973)
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                Author and article information

                Contributors
                Journal
                Arch Biochem Biophys
                Arch. Biochem. Biophys
                Archives of Biochemistry and Biophysics
                Elsevier
                0003-9861
                1096-0384
                30 March 2019
                30 March 2019
                : 664
                : 134-148
                Affiliations
                [a ]Centre for Misfolding Disease, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, United Kingdom
                [b ]Cavendish Laboratory, University of Cambridge, Cambridge, CB3 0HE, United Kingdom
                [c ]Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
                Author notes
                []Corresponding author. Centre for Misfolding Disease, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, United Kingdom. fsr26@ 123456cam.ac.uk
                [∗∗ ]Corresponding author. Centre for Misfolding Disease, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, United Kingdom. tpjk2@ 123456cam.ac.uk
                Article
                S0003-9861(18)30933-0
                10.1016/j.abb.2019.02.001
                6420408
                30742801
                © The Authors. Published by Elsevier Inc.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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