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Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease

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Abstract

Rapidly progressive Alzheimer’s disease (rpAD) is a particularly aggressive form of Alzheimer’s disease, with a median survival time of 7–10 months after diagnosis. Why these patients have such a rapid progression of Alzheimer’s disease is currently unknown. To further understand pathological differences between rpAD and typical sporadic Alzheimer’s disease (sAD) we used localized proteomics to analyze the protein differences in amyloid plaques in rpAD and sAD. Label-free quantitative LC–MS/MS was performed on amyloid plaques microdissected from rpAD and sAD patients (n = 22 for each patient group) and protein expression differences were quantified. On average, 913 ± 30 (mean ± SEM) proteins were quantified in plaques from each patient and 279 of these proteins were consistently found in plaques from every patient. We found significant differences in protein composition between rpAD and sAD plaques. We found that rpAD plaques contained significantly higher levels of neuronal proteins (p = 0.0017) and significantly lower levels of astrocytic proteins (p = 1.08 × 10−6). Unexpectedly, cumulative protein differences in rpAD plaques did not suggest accelerated typical sAD. Plaques from patients with rpAD were particularly abundant in synaptic proteins, especially those involved in synaptic vesicle release, highlighting the potential importance of synaptic dysfunction in the accelerated development of plaque pathology in rpAD. Combined, our data provide new direct evidence that amyloid plaques do not all have the same protein composition and that the proteomic differences in plaques could provide important insight into the factors that contribute to plaque development. The cumulative protein differences in rpAD plaques suggest rpAD may be a novel subtype of Alzheimer’s disease.

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Acknowledgements

The authors are grateful to the patient’s families, the CJD Foundation, and all the members of the National Prion Disease Pathology Surveillance Center for their help. This study was supported by the following Grants: NS074317, U51 CK000309, AG08051, AG20245, NS073502, the Spitz Family Foundation Grant and a Seix Dow Foundation Grant.

Author contributions

ED and TW conceived and supervised the project. ED, SN, AF, GP and RH performed the experiments. BU supervised the proteomics experiments. MA, SN and BU performed the proteomics data analysis, TW, JS, MC, TH and CK performed neuropathology, characterized and classified all cases, and sampled the brain tissue. ED, SN, MA, XH, YS, BU and TW analyzed the data. ED and TW wrote the paper with input from all authors.

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Authors and Affiliations

  1. Department of Neurology, Center for Cognitive Neurology, NYU School of Medicine, New York, NY, USA

    Eleanor Drummond, Arline Faustin, Geoffrey Pires & Thomas Wisniewski

  2. Proteomics Laboratory, Division of Advanced Research Technologies, NYU School of Medicine, New York, NY, USA

    Shruti Nayak & Beatrix Ueberheide

  3. Department of Pathology, NYU School of Medicine, New York, NY, USA

    Richard A. Hickman & Thomas Wisniewski

  4. Biomedical Hosting LLC, Arlington, MA, USA

    Manor Askenazi

  5. Departments of Pathology and Neurology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA

    Mark Cohen, Tracy Haldiman, Chae Kim & Jiri G. Safar

  6. Departments of Population Health and Environmental Medicine, NYU School of Medicine, New York, NY, USA

    Xiaoxia Han & Yongzhao Shao

  7. Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, USA

    Beatrix Ueberheide

  8. Department of Psychiatry, NYU School of Medicine, New York, NY, USA

    Thomas Wisniewski

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  1. Eleanor Drummond
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Corresponding authors

Correspondence to Eleanor Drummond or Thomas Wisniewski.

Electronic supplementary material

Below is the link to the electronic supplementary material.

401_2017_1691_MOESM1_ESM.pdf

Supplementary material 1 (PDF 224 kb). Supplementary Figure 1: Sequence alignment of detected peptides mapped to POTEE and ACTBM. Sequence alignment was performed using Clustal Omega. Detected peptides are highlighted in yellow. Amino acid differences between POTEE and ACTBM are shown in red. The table lists identified peptides mapped to POTEE, whether each peptide is also found in ACTBM or any other actin isoforms and their corresponding average LFQ intensity values in rpAD and sAD plaques.

401_2017_1691_MOESM2_ESM.xlsx

Supplementary material 2 (XLSX 2312 kb). Supplementary Table 1: LC-MS/MS results of all proteins present in plaques. The first tab shows imputed data. All results discussed in this paper were generated using this dataset. Relative protein abundance was quantified using MaxQuant. Data shows Log2 transformed LFQ intensities with missing values imputed from normal distribution. This also contains comparison with the in-house developed Alzheimer’s protein database. ALZproteins column identifies the number of proteins in the protein group that are also present in the Alzheimer’s protein database. ALZscore lists the total number of previous studies that a protein group was significantly associated with Alzheimer’s disease in the Alzheimer’s disease database (i.e. the higher the number, the more associated with Alzheimer’s disease the protein group). ALZdetails shows the breakdown of how a protein group has been previously associated with Alzheimer’s disease; U – up-regulated in previous Alzheimer’s disease studies; D – down-regulated in previous Alzheimer’s disease studies; N – enriched in neurofibrillary tangles; P – enriched in plaques. ALZdirection gives the overall annotation for the whole protein group as either up (U) or down-regulated (D) in Alzheimer’s disease. Data in the second tab (labeled unimputed data) shows LFQ intensities of all the proteins identified with 2 or more unique + razor peptides per proteins.

401_2017_1691_MOESM3_ESM.xlsx

Supplementary material 3 (XLSX 228 kb). Supplementary Table 2: Proteins present in plaques in all 44 cases examined. The list of all quantified proteins was filtered to include only proteins that had measurable expression in all plaques before imputation. Proteins are sorted by average expression in rpAD plaques. Proteins with novel involvement in AD have an “ALZproteins” score of 0.

401_2017_1691_MOESM4_ESM.xlsx

Supplementary material 4 (XLSX 121 kb). Supplementary Table 3: Proteins with significantly altered expression in rpAD plaques. The list of all proteins with significantly altered expression in rpAD plaques, sorted by –Log Welch’s t-test p-value rpAD_sAD. Proteins with a positive Welch’s t-test difference have significantly higher expression in rpAD plaques. This also contains comparison with the in-house developed Alzheimer’s protein database (see Supplementary Table 1 figure legend for details).

401_2017_1691_MOESM5_ESM.xlsx

Supplementary material 5 (XLSX 260 kb). Supplementary Table 4: Protein expression in formic acid treated tissue blocks vs non-formic acid treated tissue blocks. Data shows Log2 transformed LFQ intensities with missing values imputed from normal distribution.

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Drummond, E., Nayak, S., Faustin, A. et al. Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease. Acta Neuropathol 133, 933–954 (2017). https://doi.org/10.1007/s00401-017-1691-0

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