The Potential Role of Cytokines and Growth Factors in the Pathogenesis of Alzheimer’s Disease
Abstract
:1. Introduction
2. Immune Response in AD: Role of Cytokines
2.1. Immune System in AD and Cytokines
2.2. Roles of Cytokines in Autophagy
2.3. Cytokines and BBB
3. Role of Cytokines and Chemokines in Neuropsychiatry
4. Neuroinflammation
4.1. Pro-Inflammatory Cytokines
4.2. Anti-Inflammatory Cytokines
4.3. APP Protein
4.4. TAU
4.5. Glial Cells
4.6. Advanced Glycation End Products
4.7. Complement System
5. MMIFs in AD: Pathogenic or Protective?
6. Choroid Plexus Growth Factors and AD
6.1. Vascular Endothelial Growth Factors (VEGFs)
6.2. Fibroblast Growth Factors (FGF)
7. Neurotrophic Factors
8. Hematopoietic Growth Factors
9. Potential Strategies Involving Cytokines for Management of AD
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
ADAM | A disintegrin and metalloprotease |
AICD | APP intracellular domain |
APH-1 | Anterior pharynx defective-1 |
ApoE | Apolipoprotein E |
APP | Myloid precursor 69 protein |
Aβ | Amyloid-beta |
basic FGF/FGF2 | Basic fibroblast growth factor |
BBB | Blood-brain barrier |
BDNF | Brain-derived neurotrophic factor |
CDK5 | Cyclin-dependent kinase 5 |
CNS | Central nervous system |
CPLA2 | Cytosolic phospholipase A2 |
CSF | Cerebrospinal fluid |
DAMP | Danger-associated molecular pathways |
GCSF | Granulocyte colony-stimulating factor |
GDNF | Glial cell line-derived neurotrophic factor |
GFAP | Glial fibrillary acidic protein |
GMCSF | Granulocyte macrophage colony-stimulating factor |
GSK-3β | Glycogen synthase kinase-3beta |
IGF | Insulin-like growth factor |
IL-1ra | IL-1 receptor antagonist |
IL | Interleukin |
INF | Interferon |
LIFRb | Leukemia inhibitory factor receptor b |
LPS | Lipopolysaccharide |
MCI | Mild cognitive impairment |
MCP1 | Monocyte chemoattractant protein 1 |
MCSF | Macrophage colony-stimulating factor |
MIIB | Myosin IIB |
MIP | Macrophage inflammatory protein |
MMIF | Macrophage migration inhibitory factor |
NGF | Nerve growth factors |
p38-MAPK | Mitogen-activated protein kinases |
p75NTR | p75 neurotrophin receptor |
Pen-2 | Presenilin enhancer-2 |
PNS | Peripheral nervous system |
PSEN | Presenilin |
ROS | Reactive oxygen species |
TACE | TNF-α converting enzyme |
TGFβ | Transforming growth factor beta |
TNFs | Tumor necrosis factors |
TrK | Tropomyosin Receptor Kinases |
VEGF | Vascular endothelial growth factor |
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Serial. No. | Stages | Pathological Symptoms |
---|---|---|
1 | Early onset AD/MCI | Impairment of non-memory features of cognition, difficulty in word finding, decline in reasoning/judgement. |
2 | Mild AD | Loss of spontaneity, memory loss, anxiety, aggression, restlessness, altered personality, misplacing items. |
3 | Moderate AD | Confusion, attention deficit, continuous cognition problems, impulsive behavior, delusion, paranoia, hallucination, recognition problem. |
4 | Severe AD | Severe dementia, continued cognitive decline, seizures, functional limitations, lack of bowel/bladder control, weight loss, skin infection, swallowing difficulty, enhanced sleep time, brain atrophy. |
Serial No. | Mediators | Functions | References |
---|---|---|---|
1 | IL-1α | Increases α-secretase, decreases amyloidogenic processing, increases sAPPα | [24,26,27] |
2 | IL-1β | Increases APP mRNA, increases α-secretase and γ-secretase, downregulates β-secretase, upregulates TAU mRNA | [28,29,30] |
3 | IL-4 | Upregulates Aβ production, increases p-TAU | [30,31] |
4 | IL-6 | Upregulates APP mRNA, increases p-TAU | [10,32] |
5 | IL-8/CXCL8 | Upregulates γ-secretase activity by increasing substrates C83 and C99 | [33,34] |
6 | IL-10 | Favors Aβ deposition | [10,35,36] |
7 | IL-18 | Increases APP, upregulates both β-secretase and γ-secretase, increases Aβ formation | [10,37,38] |
8 | TNF-α | Upregulates APP mRNA, upregulates both β-secretase and γ-secretase, increases sAPPβ | [10,36,39] |
9 | IFN-γ | Upregulates APP intracellular domains, upregulates both β-secretase and γ-secretase, increases Aβ deposition | [40,41,42,43] |
10 | TGF-β1 | Increases APP mRNA, increases Aβ deposition | [10,42,43] |
11 | CCL2 | Increases Aβ formation and deposition | [44,45] |
12 | CCL3 | Upregulates β-secretase, increases C99, increases Aβ deposition | [45,46] |
13 | CCL5 | Upregulates β-secretase, increase C99, increases Aβ deposition | [46,47] |
14 | CXCL10 | Decreases Aβ deposition | [34,48] |
15 | CX3CL1 | Decreased Aβ deposition, upregulated p-TAU | [49,50] |
16 | VEGF | Upregulates expressions of monocytes and macrophages, increases proliferation of endothelial cells | [51,52,53] |
17 | FGF | Attenuates Aβ related pathologies | [52,54] |
18 | NGF | Increases degeneration leads to loss of cholinergic nerve endings in cortex and hippocampus | [55,56] |
19 | BDNF | Upregulates sAPPα, promotes non-amyloidogenic pathway, astrocyte activation, improved memory performance | [57,58] |
20 | GDNF | Neuroprotection | [55,59] |
21 | GCSF | Induces neurogenesis | [60,61] |
22 | Stem cell factor | Maintains hematopoietic brain support, neurogenesis | [62,63] |
23 | SDF | Neurogenesis, inflammatory disruption of BBB | [64,65] |
24 | CXCR4 | Ligand for SDF-1 | [64,66] |
25 | Angiopoeitins | Angiopoeitin-1 prevents neuronal apoptosis, Angiopoeitin-2 promotes neurogenesis via migration of neural progenitor cells | [67,68,69] |
26 | Neurotrophin-3 | Upregulates neuronal apoptosis inhibitory protein 1, limits cleavage of caspases 3, 8 and 9 | [70,71] |
27 | Neurotrophin-4 | Regulates TAU dephosphorylation | [70,72] |
28 | TrKA | Receptor protein for β-NGF | [73,74] |
29 | TrKB | Receptor protein for brain derived neurotrophic factor and neurotrophins | [73,75] |
30 | TrKC | Receptor protein for neurotrophin-3 | [73,76] |
31 | p75 | Neurotrophin receptor protein, regulates phosphorylation of TAU | [71,72] |
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Ogunmokun, G.; Dewanjee, S.; Chakraborty, P.; Valupadas, C.; Chaudhary, A.; Kolli, V.; Anand, U.; Vallamkondu, J.; Goel, P.; Paluru, H.P.R.; et al. The Potential Role of Cytokines and Growth Factors in the Pathogenesis of Alzheimer’s Disease. Cells 2021, 10, 2790. https://doi.org/10.3390/cells10102790
Ogunmokun G, Dewanjee S, Chakraborty P, Valupadas C, Chaudhary A, Kolli V, Anand U, Vallamkondu J, Goel P, Paluru HPR, et al. The Potential Role of Cytokines and Growth Factors in the Pathogenesis of Alzheimer’s Disease. Cells. 2021; 10(10):2790. https://doi.org/10.3390/cells10102790
Chicago/Turabian StyleOgunmokun, Gilbert, Saikat Dewanjee, Pratik Chakraborty, Chandrasekhar Valupadas, Anupama Chaudhary, Viswakalyan Kolli, Uttpal Anand, Jayalakshmi Vallamkondu, Parul Goel, Hari Prasad Reddy Paluru, and et al. 2021. "The Potential Role of Cytokines and Growth Factors in the Pathogenesis of Alzheimer’s Disease" Cells 10, no. 10: 2790. https://doi.org/10.3390/cells10102790