Background: Alzheimer's disease (AD) is a neurodegenerative disease. In previous study, we discovered that methanol extract of miracle fruits seeds (MFSs) had a therapeutic effect on AD model mice.
Objective: In this research, we aimed to study the role of MFSs in alleviating amyloid-β (Aβ) deposition and further explore the possible mechanism of action of MFSs.
Methods: We used behavioral tests and various immunolabeling techniques on two AD model (Aβ transgenic model strain CL4176 of Caenorhabditis elegans and the 3 × Tg-AD mice).
Results: In CL4176, MFSs (10 μg/mL) could effectively alleviate the paralysis caused by Aβ, the Aβ plaques were significantly reduced, the transcription levels of Aβ, age-1, akt-1 and mTOR genes were significantly downregulated, and the transcription of autophagy-related gene lgg-1 was enhanced. The cognitive function of mice in the MFSs group was improved, which was related to reduced synapse loss and Aβ-positive neurons in the brain. Meanwhile, the transcription levels of amyloid-β protein precursor (AβPP), Tau, Akt and mTOR were significantly reduced. The protein expressions of PSD95, SYN1, LC3II/I and Beclin-1 were significantly increased, and the value of p62/SQSTM1, p-AKT/AKT, p-mTOR/mTOR were reduced.
Conclusions: MFSs significantly alleviates Aβ deposition in CL4176 and mice. The mechanism by which it improves cognitive function in AD mice may be related to enhanced autophagy regulated by the Akt/mTOR signaling pathway.
JiaJWeiCChenS, et al.The cost of Alzheimer's disease in China and re-estimation of costs worldwide. Alzheimers Dement2018; 14: 483–491.
2.
GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the global burden of disease study 2019. Lancet Public Health2022; 7: e105–e125.
3.
PasseriEElkhouryKMorsinkM, et al.Alzheimer's disease: treatment strategies and their limitations. Int J Mol Sci2022; 23: 13954.
4.
ZhangYChenHLiR, et al.Amyloid beta-based therapy for Alzheimer's disease: challenges, successes and future. Signal Transduct Target Ther2023; 8: 248.
5.
JiaJNingYChenM, et al.Biomarker changes during 20 years preceding Alzheimer's disease. N Engl J Med2024; 390: 712–722.
6.
GregoryJVengalasettiYVBredesenDE, et al.Neuroprotective herbs for the management of Alzheimer's disease. Biomolecules2021; 11: 543.
7.
YangZZhouDDHuangSY, et al.Effects and mechanisms of natural products on Alzheimer's disease. Crit Rev Food Sci Nutr2023; 63: 3168–3188.
8.
ChenTYKangZCYenMT, et al.Inhibitory effect of aqueous extracts from miracle fruit leaves on mutation and oxidative damage. Food Chem2015; 169: 411–416.
9.
XieJChenXTanY, et al.Anti-hyperlipidemic components of the leaves of Synsepalum dulcificum (miracle fruit). Plant Foods Hum Nutr2024; 79: 451–459.
10.
ShiYCLinKSJhaiYF, et al.Miracle fruit (Synsepalum dulcificum) exhibits as a novel anti-hyperuricaemia agent. Molecules2016; 21: 140.
11.
LiuYGFuQMaFY, et al.Application of miracle fruit leaf extracts to preparation of medicine for treating Alzheime's diseases. Patent CN107007637A.
12.
HuangXYXueLLChenTB, et al.Miracle fruit seed as a potential supplement for the treatment of learning and memory disorders in Alzheimer's disease. Front Pharmacol2022; 13: 1080753.
13.
NilssonPSaidoTC. Dual roles for autophagy: degradation and secretion of Alzheimer's disease abeta peptide. Bioessays2014; 36: 570–578.
14.
Grosso JasutkarHWasserleinEMIsholaA, et al.Adult-onset deactivation of autophagy leads to loss of synapse homeostasis and cognitive impairment, with implications for Alzheimer disease. Autophagy2024; 20: 2540–2555.
15.
TammineniPYeXFengT, et al.Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer's disease neurons. Elife2017; 6: e21776.
16.
NilssonPLoganathanKSekiguchiM, et al.Abeta secretion and plaque formation depend on autophagy. Cell Rep2013; 5: 61–69.
17.
MorcosMHutterH. The model caenorhabditis elegans in diabetes mellitus and Alzheimer's disease. J Alzheimers Dis2009; 16: 897–908.
18.
DoreKCarricoZAlfonsoS, et al.PSD-95 protects synapses from beta-amyloid. Cell Rep2021; 35: 109194.
19.
HilfikerSBenfenatiFDoussauF, et al.Structural domains involved in the regulation of transmitter release by synapsins. J Neurosci2005; 25: 2658–2669.
20.
SayreLMSmithMAPerryG. Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr Med Chem2001; 8: 721–738.
21.
PuzzoDArgyrousiEKStaniszewskiA, et al.Tau is not necessary for amyloid-beta-induced synaptic and memory impairments. J Clin Invest2020; 130: 4831–4844.
22.
ReissABArainHASteckerMM, et al.Amyloid toxicity in Alzheimer's disease. Rev Neurosci2018; 29: 613–627.
23.
FedeleE. Anti-amyloid therapies for Alzheimer's disease and the amyloid cascade hypothesis. Int J Mol Sci2023; 24: 14499.
24.
SherlockMESudarsanNStavS, et al.Tandem riboswitches form a natural boolean logic gate to control purine metabolism in bacteria. Elife2018; 7: e33908.
25.
HenekaMTGolenbockDTLatzE. Innate immunity in Alzheimer's disease. Nat Immunol2015; 16: 229–236.
26.
LoureiroJCPaisMVStellaF, et al.Passive antiamyloid immunotherapy for Alzheimer's disease. Curr Opin Psychiatry2020; 33: 284–291.
27.
ZhangYLiuYTangY, et al.Antimicrobial alpha-defensins as multi-target inhibitors against amyloid formation and microbial infection. Chem Sci2021; 12: 9124–9139.
28.
ZhengYDengYGaoJM, et al.Icariside II inhibits lipopolysaccharide-induced inflammation and amyloid production in rat astrocytes by regulating IKK/IkappaB/NF-kappaB/BACE1 signaling pathway. Acta Pharmacol Sin2020; 41: 154–162.
29.
LiCWangNZhengG, et al.Oral administration of resveratrol-selenium-peptide nanocomposites alleviates Alzheimer's disease-like pathogenesis by inhibiting abeta aggregation and regulating gut microbiota. ACS Appl Mater Interfaces2021; 13: 46406–46420.
30.
ZhouLHuangXLiH, et al.Triptolide improves Alzheimer's disease by regulating the NF-kappaB signaling pathway through the lncRNA NEAT1/microRNA 361-3p/TRAF2 axis. Exp Ther Med2023; 26: 440.
31.
HonnenS. Caenorhabditis elegans as a powerful alternative model organism to promote research in genetic toxicology and biomedicine. Arch Toxicol2017; 91: 2029–2044.
32.
LinkCD. Expression of human beta-amyloid peptide in transgenic caenorhabditis elegans. Proc Natl Acad Sci U S A1995; 92: 9368–9372.
33.
LongTChenXQinDL, et al.Ameliorative effect of Luffa cylindrica fruits on caenorhabditis elegans and cellular models of Alzheimer's disease-related pathology via autophagy induction. Phytother Res2023; 37: 4639–4654.
34.
GuoTZhangDZengY, et al.Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease. Mol Neurodegener2020; 15: 40.
35.
RoosTTGarciaMGMartinssonI, et al.Neuronal spreading and plaque induction of intracellular abeta and its disruption of abeta homeostasis. Acta Neuropathol2021; 142: 669–687.
36.
PomeshchikYVelasquezEGilJ, et al.Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction and progression of Alzheimer's disease pathogenesis. Acta Neuropathol Commun2023; 11: 150.
37.
EckmanEAClausenDMSole-DomenechS, et al.Nascent Abeta42 fibrillization in synaptic endosomes precedes plaque formation in a mouse model of Alzheimer's-like beta-amyloidosis. J Neurosci2023; 43: 8812–8824.
38.
NathSAgholmeLKurudenkandyFR, et al.Spreading of neurodegenerative pathology via neuron-to-neuron transmission of beta-amyloid. J Neurosci2012; 32: 8767–8777.
39.
LiuBKouJLiF, et al.Lemon essential oil ameliorates age-associated cognitive dysfunction via modulating hippocampal synaptic density and inhibiting acetylcholinesterase. Aging (Albany NY)2020; 12: 8622–8639.
40.
Deleyto-SeldasNEfeyanA. The mTOR-autophagy axis and the control of metabolism. Front Cell Dev Biol2021; 9: 655731.
41.
YangHRudgeDGKoosJD, et al.mTOR kinase structure, mechanism and regulation. Nature2013; 497: 217–223.
42.
XuFNaLLiY, et al.Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci2020; 10: 54.
43.
LevineBKroemerG. Biological functions of autophagy genes: a disease perspective. Cell2019; 176: 11–42.
44.
FangEFHouYPalikarasK, et al.Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci2019; 22: 401–412.
45.
WaniAAl RihaniSBSharmaA, et al.Crocetin promotes clearance of amyloid-beta by inducing autophagy via the STK11/LKB1-mediated AMPK pathway. Autophagy2021; 17: 3813–3832.
46.
KumarSAkhilaPVSuchiangK. Hesperidin ameliorates amyloid-beta toxicity and enhances oxidative stress resistance and lifespan of caenorhabditis elegans through acr-16 mediated activation of the autophagy pathway. Free Radic Biol Med2023; 209: 366–380.
47.
WangXJiaJ. Magnolol improves Alzheimer's disease-like pathologies and cognitive decline by promoting autophagy through activation of the AMPK/mTOR/ULK1 pathway. Biomed Pharmacother2023; 161: 114473.
48.
ChenMLHongCGYueT, et al.Inhibition of miR-331-3p and miR-9-5p ameliorates Alzheimer's disease by enhancing autophagy. Theranostics2021; 11: 2395–2409.
49.
KodaliMAttaluriSMadhuLN, et al.Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus. Aging Cell2021; 20: e13277.
50.
ShefaUJeongNYSongIO, et al.Mitophagy links oxidative stress conditions and neurodegenerative diseases. Neural Regen Res2019; 14: 749–756.
51.
QuerfurthHLeeHK. Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration. Mol Neurodegener2021; 16: 44.
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