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Interactions Among Brain-Derived Neurotrophic Factor and Neuroimmune Pathways Are Key Components of the Major Psychiatric Disorders

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Abstract

The purpose of this review is to summarize the current knowledge regarding the reciprocal associations between brain-derived neurotrophic factor (BDNF) and immune-inflammatory pathways and how these links may explain the involvement of this neurotrophin in the immune pathophysiology of mood disorders and schizophrenia. Toward this end, we delineated the protein–protein interaction (PPI) network centered around BDNF and searched PubMed, Scopus, Google Scholar, and Science Direct for papers dealing with the involvement of BDNF in the major psychosis, neurodevelopment, neuronal functions, and immune-inflammatory and related pathways. The PPI network was built based on the significant interactions of BDNF with neurotrophic (NTRK2, NTF4, and NGFR), immune (cytokines, STAT3, TRAF6), and cell–cell junction (CTNNB, CDH1) DEPs (differentially expressed proteins). Enrichment analysis shows that the most significant terms associated with this PPI network are the tyrosine kinase receptor (TRKR) and Src homology region two domain-containing phosphatase-2 (SHP2) pathways, tyrosine kinase receptor signaling pathways, positive regulation of kinase and transferase activity, cytokine signaling, and negative regulation of the immune response. The participation of BDNF in the immune response and its interactions with neuroprotective and cell–cell adhesion DEPs is probably a conserved regulatory process which protects against the many detrimental effects of immune activation and hyperinflammation including neurotoxicity. Lowered BDNF levels in mood disorders and schizophrenia (a) are associated with disruptions in neurotrophic signaling and activated immune-inflammatory pathways leading to neurotoxicity and (b) may interact with the reduced expression of other DEPs (CTNNB1, CDH1, or DISC1) leading to multiple aberrations in synapse and axonal functions.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

BD:

Bipolar disorder

CDH:

Cadherin gene/protein

CDC:

Cell division cycle gene/protein

ChIP analysis:

Chromatin immunoprecipitation analysis

CIRS:

Compensatory immune regulatory system

CPE:

Carboxypeptidase E

CSF:

Cerebrospinal fluid

CRK:

CRK proto-oncogene

CREB:

CAMP response element-binding protein

CTNNB:

Catenin beta protein

CTBBB1:

Catenin beta 1 gene

DBS:

Deep brain stimulation

DISC1:

Disrupted in schizophrenia 1 protein

DEPs:

Differentially expressed proteins

FEP:

First-episode psychosis

FES:

First-episode schizophrenia

GABA:

Gamma aminobutyric acid

GO:

Gene ontology

GSK:

Glycogen synthase kinase

GRB2:

Growth factor receptor-bound protein 2

HDAC:

Histone deacetylase

HMGB1:

High mobility group box 1 DNA-binding nuclear protein

HRAS:

GTPase HRas

Hp:

Haptoglobin

hESC-NSCs:

Human embryonic spinal cord NSCs

IFN:

Interferon

IL:

Interleukin

IRS:

Inflammatory response system

JAK-STAT:

Janus kinases/signal transducer and activator of transcription

JNK:

C-Jun N-terminal kinase

KEGG:

Kyoto encyclopedia of genes and genomes

LIMK1:

LIM domain kinase 1

LPS:

Lipopolysaccharide

LTD:

Long-term depression

LTP:

Long-term potentiation

MAPK:

Ras-mitogen-activated protein kinase

MDD:

Major depressive disorder

MECP2:

Methyl-CpG-binding protein 2

MFB:

Medial forebrain bundle

MMP:

Matrix metalloproteinase

NMDAR:

N-Methyl-D-aspartate receptor

NGF:

Beta-nerve growth factor

NGFR:

Tumor necrosis factor receptor superfamily member 16

NPC:

Intracellular cholesterol transporter

NSC:

Neural stem cells

NTF:

Neurotrophin

NTRK1:

High affinity nerve growth factor receptor

NTRK2:

BDNF/NT-3 growth factors receptor

PBMC:

Peripheral blood mononuclear cells

PFC:

Prefrontal cortex

PI3K:

Phosphatidylinositol-3-kinase

PIK3R:

Phosphatidylinositol-3-kinase receptor

PLC:

Phospholipase C

PPI:

Protein-protein interaction

qRT-PCR:

Real-time quantitative reverse transcription

RAGE:

Receptor for advanced glycation end products

RIP2:

Serine/threonine protein kinase 2

SHP2:

Two domain-containing phosphatase-2

STAT3:

Signal transducer and activator of transcription 3

STRING:

Significant database-annotated interactions

SORT:

Sortilin

Th:

T helper cells

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TNFR:

Tumor necrosis factor receptor

TP53:

Tumor protein p53

TRAF6:

Tumor necrosis factor 6 receptor factor

T reg:

T regulatory cells

TRK:

Tropomyosin receptor kinase

TRKR:

Tyrosine kinase receptor

TRYCAT:

Tryptophan catabolite

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Funding

The work was supported by the National University Complex for Biomedical and Applied Research, with participation in BBMRI-ERIC (NUCBPI-BBMRI.BG), within the national road map for research infrastructure (Contract No. DO1-395/18.12.2020).

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  1. Department of Medical Biology, Medical University of Plovdiv, Plovdiv, Bulgaria

    Nikolay Mehterov, Danail Minchev, Maria Gevezova & Victoria Sarafian

  2. Research Institute at Medical University of Plovdiv, Plovdiv, Bulgaria

    Nikolay Mehterov, Danail Minchev, Maria Gevezova & Victoria Sarafian

  3. Faculty of Medicine, Department of Psychiatry, Chulalongkorn University, Bangkok, 10330, Thailand

    Michael Maes

  4. Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria

    Michael Maes

  5. Department of Psychiatry, IMPACT Strategic Research Centre, Deakin University, Geelong, VIC, Australia

    Michael Maes

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Mehterov, N., Minchev, D., Gevezova, M. et al. Interactions Among Brain-Derived Neurotrophic Factor and Neuroimmune Pathways Are Key Components of the Major Psychiatric Disorders. Mol Neurobiol 59, 4926–4952 (2022). https://doi.org/10.1007/s12035-022-02889-1

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