Proteomic signatures of neuroinflammation in Alzheimer’s disease, multiple sclerosis and ischemic stroke

ABSTRACT

Introduction: Inflammation is integral in the neuropathology of both chronic and acute neurological disorders. Knowing the inflammatory profile is important for clarification of disease mechanisms, diagnostic purposes, and ultimately treatment options.

Areas covered: A systematic review was performed on literature from PubMed using the search terms ‘Alzheimer’s disease’ (AD) or ”multiple sclerosis” (MS) or ”ischemic stroke” and ‘proteomics’. Inflammatory proteins were assessed in blood, cerebrospinal fluid (CSF), and post-mortem brain tissue. Regulated inflammatory proteins across compartments and disorders mainly consisted of innate immune proteins, acute phase proteins and oxidative stress response proteins. In addition, immunoglobulin chains were signature proteins of MS, reflecting additional involvement of adaptive immunity. The Chitinase 3-like protein 1 was increased in ten original articles on MS and in three on AD supporting its implication in these diseases. Furthermore, CNS/CSF AD inflammatory proteins were matched to a CNS myeloid cell proteome implicating Alpha-2-Macroglobulin and Annexin A1 in AD pathogenesis.

Expert opinion: Proteomics is an excellent technique for profiling inflammatory proteins in tissues and cells, but still targeted approaches are required for profiling of very low abundance proteins and peptides. Knowing the inflammatory signature of brain tissue, CSF, blood, and CNS myeloid cells holds the potential to point to novel mechanistic aspects of neurological diseases.

KEYWORDS:

• Alzheimer’s disease
• CNS myeloid cells
• complement system
• immunoglobulin
• innate immunity
• ischemic stroke
• mass spectrometry-based proteomics
• microglia
• multiple sclerosis
• neuroinflammation

Article highlights

• Neuroinflammation is an integral part of the pathology of Alzheimer’s disease (AD), multiple sclerosis (MS), and ischemic stroke.

• A unique presence of immunoglobulin chains in CSF in MS reflects the involvement of adaptive immunity.

• Increased levels of CHI3L1 in CSF of MS and AD likely reflect astrocyte involvement.

• The risk genes A2M, CHGA, CLU, and SIRT2 are increased in AD CSF

• A2M was increased across compartments in AD and in disease-associated CNS myeloid cells from APP_swe/PS1_ΔE9 mice.

• Cytokines and chemokines are under-represented in mass spectrometry-based original articles due to their small size and low abundance.

• Proteomics studies of blood and CSF are complicated by a large dynamic concentration range of proteins in these compartments.

• The post-mortem interval influences the proteomics outcome when analyzing brains from deceased human subjects.

• A high biological variability when working with human samples emphasizes the need for larger cohorts and standardized reference proteomes.

• Merging information about signature proteins of CNS tissues and cells holds great potential in identifying novel mechanistic aspects of AD, MS, and ischemic stroke.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplemental online material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by SDU2020, Fonden til Lægevidenskabens Fremme, Aase og Ejnar Danielsens Fond, Fonden for Neurologisk forskning, Kong Christian den Tiendes Fond, Scleroseforeningen and the Danish MRC.