Abstract
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, affecting over 27 million people worldwide. AD represents a complex neurological disorder which is best understood as the consequence of a number of interconnected genetic and lifestyle variables, which culminate in multiple changes to brain structure and function. These can be observed on a gross anatomical level in brain atrophy, microscopically in extracellular amyloid plaque and neurofibrillary tangle formation, and at a functional level as alterations of metabolic activity. At a molecular level, metal dyshomeostasis is frequently observed in AD due to anomalous binding of metals such as Iron (Fe), Copper (Cu), and Zinc (Zn), or impaired regulation of redox-active metals which can induce the formation of cytotoxic reactive oxygen species and neuronal damage. Metal chelators have been administered therapeutically in transgenic mice models for AD and in clinical human AD studies, with positive outcomes. As a result, neuroimaging of metals in a variety of intact brain cells and tissues is emerging as an important tool for increasing our understanding of the role of metal dysregulation in AD. Several imaging techniques have been used to study the cerebral metallo-architecture in biological specimens to obtain spatially resolved data on chemical elements present in a sample. Hyperspectral techniques, such as particle-induced X-ray emission (PIXE), energy dispersive X-ray spectroscopy (EDS), X-ray fluorescence microscopy (XFM), synchrotron X-ray fluorescence (SXRF), secondary ion mass spectrometry (SIMS), and laser ablation inductively coupled mass spectrometry (LA-ICPMS) can reveal relative intensities and even semi-quantitative concentrations of a large set of elements with differing spatial resolution and detection sensitivities. Other mass spectrometric and spectroscopy imaging techniques such as laser ablation electrospray ionization mass spectrometry (LA ESI-MS), MALDI imaging mass spectrometry (MALDI-IMS), and Fourier transform infrared spectroscopy (FTIR) can be used to correlate changes in elemental distribution with the underlying pathology in AD brain specimens. Taken together, these techniques provide new techniques to probe the pathobiology of AD and pave the way for identifying new therapeutic targets. The current review aims to discuss the advantages and challenges of using these emerging elemental and molecular imaging techniques, and highlight clinical achievements in AD research using bioimaging techniques.
Highlights
Alzheimer’s disease (AD) is the most common progressive age-related neurodegenerative disorder, affecting about 2% of the population in the developed world (Mattson, 2004)
COMBINED BIOIMAGING TECHNIQUES IN TISSUE SECTIONS Complementary information regarding the role, uptake, transport, and storage of redox active metals associated with irregular protein abnormalities can be obtained using a combination of elemental imaging techniques, such as LA-ICPMS, and other biomolecular mass spectrometry imaging techniques such as laser ablation coupled with electrospray ionization mass spectrometry (LA-ESI-MS) or MALDI-IMS
Bioimaging techniques are important for elucidating the role of metals in neurodegenerative diseases generally and AD in particular
Summary
Alzheimer’s disease (AD) is the most common progressive age-related neurodegenerative disorder, affecting about 2% of the population in the developed world (Mattson, 2004). The toxicity of Aβ is linked to changes in its structure from the soluble α-helical form to the insoluble β-pleated sheet form with consequent plaque formation, in which metals such as copper, zinc and iron are sequestered (Lovell et al, 1998a).
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