ABSTRACT

Keywords: nanomedicine, nanoimaging, atomic force microscopy, AFM, force spectroscopy, amyloids, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease

complexities involved in the formation of protein nanoparticles with different morphologies (e.g., the nanopores) in vivo. A clear understanding of the molecular mechanisms of misfolding and aggregation might facilitate development of rational approaches to prevent pathologies mediated by protein misfolding. The conventional tools currently available to researchers can only provide a snapshot of a living system, whereas much of the subtle or short-lived information is unattainable. Existing and emerging nanotools may help solve these problems by opening entirely novel avenues for the development of early diagnostic and therapeutic approaches. This chapter focuses on the application of atomic force microscopy (AFM), a fundamental technique of nanotechnology that can address protein misfolding problems. 21.2 Protein Misfolding and DiseasesMisfolding and aggregation of proteins link a number of important human health problems associated with protein deposition diseases, including neurodegenerative disorders such as Parkinson’s disease, Down’s syndrome, Alzheimer’s, Huntington’s disease, systemic and localized amyloidoses, and transmissible encephalopathies [1]. The primary and perhaps most important causative elements in most neurodegenerative processes are misfolded and aggregated proteins. Misfolded or aggregated proteins induce cellular stress and activate immunity in neurodegenerative diseases, which result in neuronal dysfunction and cell death. The accumulation of abnormal protein aggregates exerts toxicity by disrupting intracellular transport, overwhelming protein degradation pathways, and/or disturbing vital cell functions. In addition, the formation of inclusion bodies is known to represent a primary problem associated with the recombinant production of therapeutic proteins [2]. Formulation of these therapeutic proteins into delivery systems and their in vivo delivery are often complicated by protein association [3]. Finally, since protein refolding is frequently accompanied by transient association of partially folded intermediates, the propensity to aggregate is considered a general characteristic of the majority of partially folded proteins [1, 4, 5]. Thus, protein folding abnormalities and subsequent events underlie a multitude of pathologies and

difficulties associated with protein therapeutic applications. Current demographic trends indicate the need for age-related and other degenerative disorder therapeutics; and macromolecular therapeutics will be at the forefront of future medical developments. The field of medicine therefore can be dramatically advanced by establishing a fundamental understanding of key factors leading to the misfolding and self-aggregation of proteins involved in various protein folding pathologies.