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Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer's disease patients.

ABSTRACT: Neuritic plaques and neurofibrillary tangles are crucial morphological criteria for the definite diagnosis of Alzheimer's disease. We evaluated 12 unstained frontal cortex and hippocampus samples from 3 brain donors with Alzheimer's disease and 1 control with hyperspectral Raman microscopy on samples of 30 × 30 µm. Data matrices of 64 × 64 pixels were used to quantify different tissue components including proteins, lipids, water and beta-sheets for imaging at 0.47 µm spatial resolution. Hierarchical cluster analysis was performed to visualize regions with high Raman spectral similarities. The Raman images of proteins, lipids, water and beta-sheets matched with classical brain morphology. Protein content was 2.0 times, the beta-sheet content 5.6 times and Raman broad-band autofluorescence was 2.4 times higher inside the plaques and tangles than in the surrounding tissue. The lipid content was practically equal inside and outside. Broad-band autofluorescence showed some correlation with protein content and a better correlation with beta-sheet content. Hyperspectral Raman imaging combined with hierarchical cluster analysis allows for the identification of neuritic plaques and neurofibrillary tangles in unstained, label-free slices of human Alzheimer's disease brain tissue. It permits simultaneous quantification and distinction of several tissue components such as proteins, lipids, water and beta-sheets.

SUBMITTER: Michael R

PROVIDER: S-EPMC5688091 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Granulovacuolar degeneration (GVD) is a common feature in Alzheimer's disease (AD). The occurrence of GVD is closely associated with that of neurofibrillary tangles (NFTs) and GVD is even considered to be a pre-NFT stage in the disease process of AD. Currently, the composition of GVD bodies, the mechanisms associated with GVD and how GVD exactly relates to NFTs is not well understood. By combining immunohistochemistry (IHC) and laser microdissection (LMD) we isolated neurons with GVD and those bearing tangles separately from human post-mortem AD hippocampus (n = 12) using their typical markers casein kinase (CK)1δ and phosphorylated tau (AT8). Control neurons were isolated from cognitively healthy cases (n = 12). 3000 neurons per sample were used for proteome analysis by label free LC-MS/MS. In total 2596 proteins were quantified across samples and a significant change in abundance of 115 proteins in GVD and 197 in tangle bearing neurons was observed compared to control neurons. With IHC the presence of PPIA, TOMM34, HSP70, CHMP1A, TPPP and VXN was confirmed in GVD containing neurons. We found multiple proteins localizing specifically to the GVD bodies, with VXN and TOMM34 being the most prominent new protein markers for GVD bodies. In general, protein groups related to protein folding, proteasomal function, the endolysosomal pathway, microtubule and cytoskeletal related function, RNA processing and glycolysis were found to be changed in GVD neurons. In addition to these protein groups, tangle bearing neurons show a decrease in ribosomal proteins, as well as in various proteins related to protein folding. This study, for the first time, provides a comprehensive human based quantitative assessment of protein abundances in GVD and tangle bearing neurons. In line with previous functional data showing that tau pathology induces GVD, our data support the model that GVD is part of a pre-NFT stage representing a phase in which proteostasis and cellular homeostasis is disrupted. Elucidating the molecular mechanisms and cellular processes affected in GVD and its relation to the presence of tau pathology is highly relevant for the identification of new drug targets for therapy.

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Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer's disease patients.

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