Neurodegenerative diseases (NDs) are common chronic diseases typically characterized by a progressive loss of function and death of neurons in the brain or peripheral nervous system. NDs are among the most widespread health problems, affecting millions of people worldwide. The potential to treat NDs of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs.
Disease | Misfolded Protein(s) |
Cell Types Primarily Affected | Clinical Feature(s) |
---|---|---|---|
Alzheimer’s disease (AD) | Aβ, tau | Hippocampal neurons | Dementia |
Parkinson’s disease (PD) | α-syn | Substantia nigra Dopaminergic neuron |
Parkinsonism |
Multiple system atrophy (MSA) | α-syn | Basal ganglia and/or cerebellar oligodendrocytes | Parkinsonism and/or ataxia |
Dementia with Lewy bodies (DLB) | α-syn | Cortical and/or hippocampal and/or striatal neurons | Dementia and/or parkinsonism |
Huntington disease (HD) | huntingtin | Striatal neurons | Dementia |
Spinocerebellar ataxia | Ataxin | Cerebellar neurons | Cerebellar ataxia |
Amyotrophic lateral sclerosis (ALS) | Ataxin, FUS, TDP43, C9orf72 or superoxide dismutase 1 (SOD1) | Motor neurons | Muscular atrophy |
Frontotemporal dementia | FUS, TDP43, C9orf72 or SOD1 | Cortical neurons | Dementia |
Gerstmann–Sträussler– Scheinker syndrome (GSS) | Prion protein | Cerebellar neurons | Ataxia |
Fatal familial insomnia | Prion protein | Thalamic neurons | Insomnia |
Creutzfeldt–Jakob disease (CJD) | Prion protein | Cortical neurons | Dementia |
Experimental Models | Cell Line | Outcomes |
---|---|---|
Aβ-induced neurotoxicity model | Primary culture | Elevates cell survival and decreases the levels of malondialdehyde (MDA) and caspase activity [172] |
Paraquat-induced PD model | PC12 cells | Protects against paraquat-induced apoptosis via modulating mitochondrial function [173] |
Aβ1-42-exposure neuronal cells | Primary culture | Suppresses Aβ-induced BACE-1 upregulation [174] |
6-OHDA-induced PD model | SH-SY5Y cells | Protects against cell death through STAT3 activation [175] |
Aβ-induced oxidative and nitrosative cell death | BV2 microglia | Fortifies cellular antioxidant glutathione pool via elevated expression of γ-glutamylcysteine ligase [176] |
Human neuronal cells | MC65 cells (overexpressing APP) |
Suppresses Aβ -induced neurotoxicity by inhibiting c-Abl/FE65 nuclear translocation and GSK3β activation [177] |
ROT-injured murine brain cultures | Primary mesencephalic cell cultures | No influence on the survival of dopaminergic neurons in mesencephalic cultures [178] |
DDT-induced cell death | SH-SY5Y cells | Activates endogenous neuroprotective mechanism(s) that can protect against cell death [179] |
Fibril-induced neurotoxicity | HEK-293 cells(overexpressing α-syn)7PA2 cells(overexpressing APP)PC12 cells | Remodels mature α-syn and amyloid-β fibrils and reduces cellular toxicity [148] |
MPP+-induced PD model | PC12 cells | Suppresses oxidative stress via the SIRT1/PGC-1α signaling pathway [180] |
6-OHDA-induced PD model | N27 cells | Pretreatment with EGCG protected against neurotoxicity by regulating genes and proteins involved in brain iron homeostasis, especially modulating hepcidin levels [181] |
Microglia-mediated neuroinflammation |
EOC 13.31 | Attenuates Aβ-induced inflammation and neurotoxicity [182] |
α-syn induced neurotoxicity | α-syn transduced-PC12 cells | Protects cells against α-syn-induced damage by inhibiting the overexpression and fibrillation of α-syn in the cells [151] |
Cu(II)-mediated toxicity | α-syn transduced-PC12 cells | Inhibits the overexpression and fibrillation of α-syn and reduces Cu(II)-induced oxidative stress [183] |
Alzheimer’s Disease | ||
---|---|---|
Experimental Models | Animal Strain | Outcomes |
Transgenic mice overproducing Aβ | Tg APPsw (line 2576) | Decreases Aβ levels and plaque associated with promotion of the nonamyloidogenic α-secretase proteolytic pathway [184] |
Stereotaxic surgery lesion | Wistar rats | Restores β-amyloid-induced behavioral derangements relating to coordination and memory abilities [185] |
Transgenic mice overproducing Aβ | Tg APPsw (line 2576) | Provides cognitive benefit and modulates tau pathology [186] |
Transgenic mice overproducing Aβ | Tg APPsw (line 2576) | Inhibits GSK3β activation and c-Abl/Fe65 complex nuclear translocation [177]. |
LPS-induced AD model | ICR mice | Inhibition of Aβ generation through the inhibition of β- and γ-secretase activity [187] |
Aβ-induced AD model | ICR mice | Downregulates β- and γ-secretase activities and eventually decreases toxic Aβ levels in the cortex and hippocampus [188] |
D-gal-induced AD model | Kunming mice | Increases the activities of antioxidant enzymes and reduces the activation of caspase-3 [189] |
LPS-induced AD model | ICR mice | Prevents activation of astrocytes and elevation of proinflammatory cytokines including TNF-α, as well as the increase of inflammatory proteins such as inducible nitric oxide synthase (iNOS) andcyclooxygenase-2 (COX-2) [190] |
Streptozotocin-induced AD model | Wistar rats | Neuroprotective effects through reversion of oxidative stress and decreased acetylcholinesterase activity [191] |
Transgenic mice overproducing Aβ | Tg CRND8 mice | Ameliorates some behavioral manifestations and cognitive impairments [192] |
Senescence-accelerated mouse (SAM) | SAMP8 | Attenuates cognitive deterioration by upregulating neprilysin expression [193] |
Senescence-accelerated mouse (SAM) | SAMP8 | Oral consumption of EGCG ameliorates memory impairment and reduces the levels of Aβ1–42 and BACE-1 [194] |
Aluminum-induced AD model | Wistar rats | Oral administration of EGCG nanoparticles attenuates neurobehavioral deficits and Aβ and Tau pathology [195] |
Transgenic mice expressing mutant human APP and presenilin 1 |
APP/PS1 mice | Inhibition of endoplasmic reticulum stress-associated neuronal apoptosis [196] |
Transgenic mice expressing mutant human APP and presenilin 1 |
APP/PS1 mice | Combination of EGCG with ferulic acid improves behavioral deficits, ameliorating cerebral amyloidosis and reducing Aβ generation [197] |
Transgenic mice producing abundant Aβ plaques | APPswe/PS1dE9 mice | Oral administration of EGCG/ascorbic acid nanoparticles reduces Aβ plaque burden, Aβ42 peptide levels, and neuroinflammation while enhancing synaptogenesis, memory, and the learning process [198] |
Transgenic mice producing abundant Aβ plaques fed with a high-fat diet (mixed model of familial AD and T2DM) |
APPswe/PS1dE9 mice | Decreases brain Aβ production and plaque burden by increasing the levels of α-secretase and reduces neuroinflammation by the decrease in astrocyte reactivity and toll-like receptor 4 (TLR4) levels [199] |
Transgenic mice expressing mutant human APP and presenilin 1 |
APP/PS1 mice | Reduces Aβ plaques in the brain [200] |
Parkinson’s disease | ||
Experimental models | Animal strain | Outcomes |
MPTP-induced PD model | C57/BL mice | Alleviates dopamine neuron loss in the substantia nigra and tyrosine hydroxylase (TH) protein level depletion [201] |
MPTP-induced PD model | C57B6 mice | Decreases expressions of nitric oxide synthase in the substantia nigra [202] |
6-OHDA-induced PD model | Wistar rats | Reverses the striatal oxidative stress and immunohistochemistry alterations [203] |
MPTP-induced PD model | C57BL/6J mice | Regulates the iron-export protein ferroportin in substantia nigra, reduces oxidative stress, and exerts a neurorescue effect [204] |
MPTP-induced PD model | C57BL/6J mice | May exert neuroprotective effects by modulating peripheral immune response [205] |
ROT-induced PD model | Drosophila melanogaster | Ameliorates neuronal and behavioral defects by remodeling gut microbiota and turandot M (TotM) expression [206] |
ROT-induced PD model | Wistar rats | Reduces NO level and lipid peroxidation production, increases the levels of catecholamines in the striatum, and reduces the levels of neuroinflammatory and apoptotic markers [207] |
Amyotrophic lateral sclerosis | ||
Experimental models | Animal strain | Outcomes |
Transgenic mice carrying a human SOD1 with a G93A mutation | B6SJL Tg (SOD1-G93A) |
Increases the number of motor neurons and reduces the concentration of NF-kB caspase-3 and iNOS [208] |
Transgenic mice carrying a human SOD1 with a G93A mutation | B6SJL Tg (SOD1-G93A) |
Prolongs symptom onset and life span, preserving more survival signals and attenuating death signals [209] |
Huntington’s disease | ||
Experimental models | Animal strain | Outcomes |
Transgenic flies expressing mutant huntingtin fragments with 93 glutamines |
Drosophila melanogaster | Modulates early events in huntingtin misfolding and reduces toxicity [25] |
3-nitropropionic acid induced cognitive dysfunction and glutathione depletion | Wistar rats | Improves memory and restores glutathione system functioning [210] |
Familial amyloidotic polyneuropathy (FAP) | ||
Experimental models | Animal strain | Outcomes |
Transgenic mice for human TTR | Tg hTTR V30M mice | Decreases non-fibrillar TTR deposition and disaggregation of amyloid deposits [211] |
Protein | Main Outcome | Experimental Techniques |
---|---|---|
Huntingtin | Modulates misfolding and oligomerization [25] | Dot-blot and AFM |
Aβ42 α-syn |
Redirects aggregation cascades and thus prevents the formation of toxic, β-sheet–rich aggregation products [26] | ThT fluorescence, TEM, CD, and dot-blot |
Aβ42 α-syn |
Binds to β-sheet-rich aggregates remodeling mature fibrils [148] | ThT fluorescence, TEM, AFM, and CD |
α-syn | Inhibits and disaggregates oligomers [212] | Confocal single-particle fluorescence spectroscopy |
Aβ40 | Induces the formation of nontoxic well-structured oligomers [128] | Solid-state NMR and MTT assay |
Aβ40 | The amyloid remodeling activity is dependent on auto-oxidation of the EGCG [213] | ThT fluorescence, congo red assay, EM, AFM, CD, and MTT assay |
Aβ42 PrP106–126 |
Reduces the number of fibrils [214] | NMR, TEM, and CD |
α-syn | Inhibits oligomer toxicity, moderately reduces membrane binding, and immobilizing the oligomer -terminal tail [149] | Calcein release assay, LSCM, NMR, TEM, CD, DLS, SAXS, MTT assay, and ITC |
Tau | Prevents aggregation and toxicity [150] | ThT fluorescence, AFM, and MTT assay |
α-syn | Inhibits fibrillation and disaggregates amyloid fibrils [174] | ThT fluorescence, CD, NMR, AFM, and TEM |
α-syn | Aggregates showed small fibrillar length, and less toxicity correlates with reduction of exposed hydrophobic surface [215] | ThT fluorescence, CD, FTIR, ANS fluorescence, TEM, NMR, SPR, and MTT assay |
α-syn | Protects against membrane disruption and cytotoxicity caused by oligomers [131] | ThT fluorescence, tyrosine intrinsic fluorescence, TEM, CD, DLS, FTIR, AFM, and MTT assay |
Aβ40 | Remodels toxic oligomers to nontoxic aggregates [216] | DEST, NMR, ANS fluorescence, DLS, and TEM |
Aβ42 | Remodels soluble Aβ assemblies into less toxic species with less exposed hydrophobic sites [217] | Comparative analysis of N-R2 and DEST NMR combined with WAXD, TEM, DLS, and extrinsic fluorescence |
Aβ42 | Higher EGCG-to-Aβ42 ratios promote the rate of aggregation, while lower EGCG-to-Aβ42 ratios inhibit the aggregation rate [218] | ThT fluorescence, TEM and EPR |
Aβ40 | Alleviates aggregation induced by metal ions [200] | ThT fluorescence, TEM, ICP-MS, UV–Vis spectroscopy |
Tau | Dual effect on aggregation inhibition and disassembly of full-length Tau [28] | ThT fluorescence, MALDI-TOF analysis, and ITC |
α-syn | EGCG microparticles reduce the cytotoxic effects of oligomers; besides, they increase the activity of other antiamyloidogenic compounds when used together [219] | ThT fluorescence, CD, DLS, TEM, and cell viability assay |
This entry is adapted from the peer-reviewed paper 10.3390/biom11050767