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European Biopharmaceutical Review

Visualising Alzheimers

Dementia, a condition describing an array of symptoms including memory loss and cognitive degeneration, affects 47 million people worldwide (1). Alzheimer’s disease (AD), the most common cause of dementia, leads to protein build-up in the brain in the form of plaques. These plaques interfere with nerve cell connections, ultimately causing nerve cell death and brain tissue loss. For some time, the amyloid hypothesis has been described as the leading cause of AD: amyloid-β (Aβ), an insoluble peptide, has been characterised in the plaques found in the brains of patients with AD. Formation of Aβ arises from the cleavage of a much larger protein called amyloid precursor protein. Before becoming plaques, Aβ monomers (individual peptides) clump together into oligomers, which can be seen in early onset AD. These oligomers progress to form the neurotoxic plaques. Although the amyloid hypothesis has been well-understood for a number of years, the characterisation of Aβ structural assembly requires more in-depth research to improve comprehension of AD pathogenesis and better develop appropriate diagnostic and therapeutic biomarkers. Mass spectrometry-based proteomic analysis is a valuable approach that characterises the variety of Aβ species in brain tissues. Matrix-assisted laser desorption/ionisation (MALDI) imaging mass spectrometry has shown advantages compared with traditional immunohistochemistry (IHC) methods to determine the localisation of Aβs in brain tissue.

MALDI in Practice

The Department of Medical Life Systems at Doshisha University houses a leading laboratory using MALDI imaging mass spectrometry (MALDI-IMS) to advance its research across the genomics and proteomics field. The lab is pioneered by Professor Masaya Ikegawa, whose current prime focus is the deposition of Aβ in the brains of patients with AD (2). The lab aimed to characterise the distribution of individual Aβ peptides in the autopsied brains of elderly subjects, and those suffering from AD and cerebral amyloid angiopathy (CAA) (see Figure 1).

In typical Alzheimer’s neuropathy, IHC methods have been used in the past to determine the localisation of Aβ peptides in brain tissues. However, this technique cannot discriminate between different variants when a number of epitopes are used simultaneously, risking the introduction of bias. Mass spectrometry-based proteomic analysis has gained popularity as an alternative method for characterising the variety of Aβ species in the brain, and, most recently, MALDI-IMS has emerged as an important tool for investigating protein and small molecule distribution within biological systems. MALDI imaging can individually track the whole distribution of complex molecules having multiple modifications, which is an advantage over IHC. Previously, the signal could be vague, but, even with a muddy biological matrix at 100μm resolution, the MALDI imaging mass spectrometer provides high-quality results.

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Dr Shannon Cornett received his PhD in analytical chemistry from the University of Georgia, US. Following a postdoctoral with at City of Hope National Medical Centre, US he joined Bruker and worked in the roles of Applications Scientist, TOF R&D Manager, and TOF Product Manager. In 2002, Shannon moved to the Mass Spectrometry Research Facility at Vanderbilt University as Research Assistant Professor, developing new tools and methodologies for the thenemerging field of imaging mass spectrometry. He rejoined Bruker Daltonics in 2009 to support the MALDI imaging product lines and now manages the imaging business.
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