Huperzine A and Its Neuroprotective Molecular Signaling in Alzheimer’s Disease
Abstract
:1. Introduction
2. HupA within the CNS: Modulation of Critical Pathological Conditions
2.1. HupA Mediated Modulation of Amyloid-β PeptideToxicity
2.2. HupA on Dementia
3. Neuroprotective Molecular Signaling of HupA against AD
Molecular Target | Effects of HupA Treatment | References |
---|---|---|
Inhibition of AChE | Reduced neuronal loss Decreased Aβ neurotoxicity]. Attenuated p53-mediated cell death Downregulated NF-kβ signaling Downregulated p65 translocation-related neurodegeneration [ | [9,37,39,46,49] |
Activation of α7-nAChRs and α4β2-nAChRs | Decreased NF-κB signaling Increased GABAergic transmission Reduced pro-inflammatory cytokines | [31,46,47] |
Upregulation of Neurotrophin | Reduced loss of cholinergic neurons | [52] |
Activation of BDNF/TrkB | Improved neuronal survival through PI3K/TrkB/mTOR signaling Induced LTP and synaptic transmission | [48,51,52,54] |
Upregulation of Bcl-2 and downregulation of Bax | Decreased apoptotic activity | [38] |
Upregulation of Synaptotagmin | Improved synaptic vesicle exocytosis | [48] |
Interaction with ChE-like domain of Neuroligin-1 | Decreased Aβ aggregation | [37,46,60] |
Downregulation of activity of GSK-3β | Decreased tau phosphorylation and Aβ accumulation Increased neurogenesis and modulation of synaptic plasticity Increased nonamyloidogenic processing of APP] Downregulated NF-kβ signaling downregulated p65 expression-related neurodegeneration | [39,46,48,54] |
4. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AChE | Acetylcholinesterase |
AChEI | Acetylcholinesterase Inhibitor |
AD | Alzheimer´s Disease |
ADAM10 | Disintegrin and Metalloproteinase Domain-containing Protein 10 |
AIF | Apoptosis Inducing Factor |
APP | Amyloid Precursor Protein |
ATP | Adenosine Triphosphate |
Aβ | Amyloid- β peptide |
BACE1 | β-site of the APP-cleaving enzyme |
Bax | Bcl-2-like protein 4 |
BBB | Blood Brain Barrier |
Bcl-2 | Bcl-2 B-cell lymphoma-2 |
BDNF | Brain-Derived Neurotrophic Factor |
CAT | Catalase |
CNS | Central Nervous System |
CREB | Cyclic Adenosine Monophosphate Responsive Element Binding Protein |
CytoC | Cytochrome C |
GSH-PX | Glutathione Peroxidase |
GSK-3β | Glycogen Synthase Kinase-3β |
HupA | Huperzine A |
IL-6 | Interleukin-6 |
IRE | Iron-Responsive Element |
IRP-1 | Iron Regulatory Protein-1 |
MAPK/ERK | Mitogen-activated Protein Kinases/Extracellular Signal-regulated Kinases |
MIP-1α | Macrophage Inflammatory Protein-1α |
mTOR | Mammalian Target of Rapamycin |
NF-kB | Nuclear Factor Kappa-light-chain-enhancer of Activated B cells |
NL1 | Neuroligin 1 |
NMDA | N-methyl-D-aspartate |
NMDAR | N-methyl-D-aspartate Receptor |
PI3K | Phosphatidylinositol 3-Kinase |
PKC | Protein Kinase C |
PS1 | Presenilin 1 |
ROS | Reactive Oxygen Species |
SOD | Superoxide Dismutase |
TBI | Transferrin-Bound Iron |
TFR1 | Transferrin Receptor Protein 1 |
TNF-α | Tumor Necrosis Factor-α |
TrkB | Tropomyosin receptor kinase B |
VaD | Vascular-associated Dementia |
Wnt | Wingless-related Integration Site |
WT | Wild-type |
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Mechanism | Molecular Target | Effects of HupA Treatment | References |
---|---|---|---|
Mitochondrial protection | Upregulation of oxidative phosphorylation proteins | Recovered energetic homeostasis | [52] |
Inhibition of cytoplasmic translocation of CytoC | Prevented mitochondria-mediated apoptosis | [69] | |
Downregulation of AIF | Prevented cas3-independent apoptosis | [52] | |
Inhibition of Caspase-3 cleavage | Prevented cas-3 dependent apoptosis | [52] | |
Upregulation of GSH-PX SOD CAT | Decreased ROS accumulation Decreased oxidative stress | [52] | |
Fe2+ homeostasis | Chelator/ Reducer of Fe2+ | Increased nonamyloidogenic processing of APP Downregulated expression of APP through IRP-1 | [34] |
Downregulation of TFR1 | Decreased Fe2+ uptake in neurons | [34] |
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Friedli, M.J.; Inestrosa, N.C. Huperzine A and Its Neuroprotective Molecular Signaling in Alzheimer’s Disease. Molecules 2021, 26, 6531. https://doi.org/10.3390/molecules26216531
Friedli MJ, Inestrosa NC. Huperzine A and Its Neuroprotective Molecular Signaling in Alzheimer’s Disease. Molecules. 2021; 26(21):6531. https://doi.org/10.3390/molecules26216531
Chicago/Turabian StyleFriedli, María Jesús, and Nibaldo C. Inestrosa. 2021. "Huperzine A and Its Neuroprotective Molecular Signaling in Alzheimer’s Disease" Molecules 26, no. 21: 6531. https://doi.org/10.3390/molecules26216531