Mass spectrometry imaging, an emerging technology in neuropsychopharmacology

Abstract

Mass spectrometry imaging is a powerful tool for directly determining the distribution of proteins, peptides, lipids, neurotransmitters, metabolites and drugs in neural tissue sections in situ. Molecule-specific imaging can be achieved using various ionization techniques that are suited to different applications but which all yield data with high mass accuracies and spatial resolutions. The ability to simultaneously obtain images showing the distributions of chemical species ranging from metal ions to macromolecules makes it possible to explore the chemical organization of a sample and to correlate the results obtained with specific anatomical features. The imaging of biomolecules has provided new insights into multiple neurological diseases, including Parkinson's and Alzheimer's disease. Mass spectrometry imaging can also be used in conjunction with other imaging techniques in order to identify correlations between changes in the distribution of important chemical species and other changes in the properties of the tissue. Here we review the applications of mass spectrometry imaging in neuroscience research and discuss its potential. The results presented demonstrate that mass spectrometry imaging is a useful experimental method with diverse applications in neuroscience.

Figure 1

General overview of matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) imaging. Tissue sections from frozen brain are cut by a cryomicrotome and transferred to a conductive glass slide. Tissue sections are coated with a specific matrix, depending on the nature of the biomolecule to be analyzed. MALDI-MS imaging allows simultaneous mapping of hundreds of multimodal substances in thin tissue sections with a lateral resolution down to a few μm. From a raster over the tissue and measurement of the peak intensities over thousands of spots, mass spectrometric images are generated at specific molecular weight values.

Figure 2

Quantitation of endogenous substance P 1–11 (SP) concentration in a mouse brain sagittal tissue section. (a) Digital photograph of the mouse brain tissue section indicating different brain tissue structures. (b) SP was quantified in the nucleus accumbens, caudoputamen, globus pallidus external segment, substantia nigra, substantia innominata. The matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) imaging analysis shows that endogenous SP is detected at high concentrations in substantia innominata, globus pallidus external segment, and substantia nigra. (c) Mass spectrum from the substantia innominata structure showing the monoisotopic mass of SP (inset). Reproduced with permission (Kallback et al, 2012).

Figure 3

Matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) imaging relative abundance and spatial distribution of the neurotransmitter acetylcholine (m/z 146.1±0.1) in a rat brain sagittal tissue sections. The confirmation that m/z 146.1 is acetylcholine was achieved by on tissue MS/MS fragmentation, where product ions of m/z 87.0 and m/z 104.1 were generated and agreed with a MS/MS spectrum from synthetic acetylcholine. The MALDI-MS image shows that acetylcholine is most abundant in brain structures such as cerebral cortex, corpus callosum, ventral hippocampal commissure, thalamus, and cerebellum. Reproduced with permission (Shariatgorji et al, 2012b).

Figure 4

(a) Optical image and (b) matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) imaging relative abundance and distribution of potassium (m/z 39) of a rat brain coronal section. Dashed line shows the measured region and data are displayed in rainbow scale over the same range (scale bar, 5 mm). (c) The overall mass spectrum of the rat brain coronal section shows the signal of potassium and sodium ions.

Figure 5

Matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) images of (a) adenosine monophosphate (AMP), (b) adenosine diphosphate (ADP), (c) UDP-N-acetylglucosamine (UDP-GlcNac), (d) fructose-1,6-bisphosphate (F-1,6-biP), and (e) guanosine triphosphate (GTP) acquired in the negative ion mode from a rat brain section deposited on a stainless steel plate, after deposition of a homogeneous layer of 9-AA. Field of view: 8.3 × 8.3 mm², 50 μm spatial resolution. The values of intensity (I) indicated under each image correspond to the minimal and maximal intensity in a pixel. (f) Optical image of a brain tissue section after 9-aminoacridine deposition as matrix and analysis by MALDI-MS imaging with a 50 μm spatial resolution. Reproduced with permission (Benabdellah et al, 2009).

Figure 6

Matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) images of amyloid-beta peptide (Aβ) peptide distributions in mouse brain tissue section from Alzheimer's disease (AD) mouse model (APP23). Within one image acquisition, multiple Aβ peptide are measured simultaneously (individual mass peaks are used to generate separate images). Reproduced with permission (Stoeckli et al, 2006).

Figure 7

Cholesterol accumulates in the vicinity of amyloid-beta peptide (Aβ) deposits in 3 × Tg-Alzheimer's disease (AD) mouse model brain tissue sections. Images of two areas located in the superior subiculum show the time-of-flight secondary ion mass spectrometry (TOF-SIMS) cholesterol distribution (a–c) and the overlaid cholesterol/p-FTAA images (b–d) (p-FTAA is an amyloidotropic fluorescent dye that binds primarily to fibrillary Aβ). Cholesterol accumulations are highlighted by white arrowheads in (a–c). Reproduced with permission (Sole-Domenech et al, 2013)

Figure 8

Matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) imaging of brain tissue sections after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. The relative ion density of PEP-19 from one control (a) and one MPTP-treated animal (b) shows that there is a reduction of PEP-19 expression in the striatum. Adapted from Skold et al (2006).

Figure 9

Protein intensity differences between amyotrophic lateral sclerosis (ALS) and controls. (a) Protein peaks with m/z 8429 and m/z 8451 were found to be mainly abundant in the gray matter and (b) showed significant lower peak intensity in ALS patients. (c) Unpaired statistical analysis (statistical analysis of microarray data) (SAM) were used (P<0.05). Scale bar, 5 mm. Reproduced with permission (Hanrieder et al (2013).