This study aims to explore the causal relationship between five selected factors—lysosome, migrasomes, macrophage, fibroblast, and endothelium cell—and early-onset Alzheimer's disease (EOAD) through related genes, providing clues for EOAD research.
Methods
Using genes related to the five selected factors as exposure variables and EOAD as the disease outcome, significant genes were screened through Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW) method, based on the OpenGWAS database. The selected genes were intersected with genes related to the exposure factors to assess the causal relationships between the five factors and EOAD.
Results
MR analysis identified 13 genes in total. Six of these genes were protective factors for EOAD, with LYST being the most significant (OR = 0.4259, 95% CI: 0.2218–0.8178, p = 0.0103). Seven genes were risk factors for EOAD, with NCF4 being the most significant (OR = 2.7207, 95% CI: 1.0229–7.2362, p = 0.0449). A total of 1925 genes related to lysosome, migrasomes, macrophage, fibroblast, and endothelium cell were analyzed. After intersection, 10 lysosome-related genes (NCF4, VIPAS39, LYST, SORT1, ARSB, EPDR1, SYNGR1, ANXA11, PYGB, CLN5) and 3 endothelium cell -related genes (ADM, NFIB, NKTR) were found to have significant causal relationships with EOAD.
Conclusions
There are genes related to lysosome and endothelium cell that have significant relationships with EOAD, while no causal relationships were found between migrasomes, macrophage, fibroblast, and EOAD. This study provides an important basis for further EOAD research.
AyodeleTRogaevaEKurupJT, et al.Early-onset Alzheimer's disease: what is missing in research?Curr Neurol Neurosci Rep2021; 21: 4.
2.
NystuenKLMcNameeSMAkulaM, et al.Alzheimer's disease: models and molecular mechanisms informing disease and treatments. Bioengineering (Basel)2024; 11: 45.
3.
DrummondEKavanaghTPiresG, et al.The amyloid plaque proteome in early onset Alzheimer's disease and Down syndrome. Acta Neuropathol Commun2022; 10: 53.
4.
CisnerosJBeltonTBShumGC, et al.Mitochondria-lysosome contact site dynamics and misregulation in neurodegenerative diseases. Trends Neurosci2022; 45: 312–322.
5.
BarralDCStaianoLGuimas AlmeidaC, et al.Current methods to analyze lysosome morphology, positioning, motility and function. Traffic2022; 23: 238–269.
6.
PeiJWangGFengL, et al.Targeting lysosomal degradation pathways: new strategies and techniques for drug discovery. J Med Chem2021; 64: 3493–3507.
7.
ZhengHLiGMinJ, et al.Lysosome and related protein degradation technologies. Drug Discov Today2023; 28: 103767.
8.
BalistreriCRDi GiorgiLMonasteroR. Focus of endothelial glycocalyx dysfunction in ischemic stroke and Alzheimer's disease: possible intervention strategies. Ageing Res Rev2024; 99: 102362.
9.
CainATagaMMcCabeC, et al.Multicellular communities are perturbed in the aging human brain and Alzheimer's disease. Nat Neurosci2023; 26: 1267–1280.
10.
FloresJJKlebeDTangJ, et al.A comprehensive review of therapeutic targets that induce microglia/macrophage-mediated hematoma resolution after germinal matrix hemorrhage. J Neurosci Res2020; 98: 121–128.
11.
Mesquida-VenyFDel RíoJAHerveraA. Macrophagic and microglial complexity after neuronal injury. Prog Neurobiol2021; 200: 101970.
GrubmanAChooXYChewG, et al.Transcriptional signature in microglia associated with aβ plaque phagocytosis. Nat Commun2021; 12: 3015.
14.
LeeSYChoiSHKimY, et al.Migrasomal autophagosomes relieve endoplasmic reticulum stress in glioblastoma cells. BMC Biol2024; 22: 23.
15.
KöktürkSDoğanSYılmazCE, et al.Expression of brain-derived neurotrophic factor and formation of migrasome increases in the glioma cells induced by the adipokinetic hormone. Rev Assoc Med Bras (1992)2024; 70: e20231337.
16.
DorrierCEAranDHaeneltEA, et al.CNS Fibroblasts form a fibrotic scar in response to immune cell infiltration. Nat Neurosci2021; 24: 234–244.
17.
JonesHECoelho-SantosVBonneySK, et al.Meningeal origins and dynamics of perivascular fibroblast development on the mouse cerebral vasculature. Development2023; 150: dev201805.
18.
PérezMJPonceDPAranguizA, et al.Mitochondrial permeability transition pore contributes to mitochondrial dysfunction in fibroblasts of patients with sporadic Alzheimer's disease. Redox Biol2018; 19: 290–300.
19.
Tort-MerinoAFalgàsNAllenIE, et al.Early-onset Alzheimer's disease shows a distinct neuropsychological profile and more aggressive trajectories of cognitive decline than late-onset. Ann Clin Transl Neurol2022; 9: 1962–1973.
20.
MigliaccioRCacciamaniF. The temporal lobe in typical and atypical Alzheimer disease. Handb Clin Neurol2022; 187: 449–466.
21.
PhillipsMLStageECJrLaneKA, et al.Neurodegenerative patterns of cognitive clusters of early-onset Alzheimer's disease subjects: evidence for disease heterogeneity. Dement Geriatr Cogn Disord2020; 48: 131–142.
22.
GrassiSChiricozziEMauriL, et al.Sphingolipids and neuronal degeneration in lysosomal storage disorders. J Neurochem2019; 148: 600–611.
23.
WhyteLSLauAAHemsleyKM, et al.Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?J Neurochem2017; 140: 703–717.
24.
ZoncuRPereraRM. Built to last: lysosome remodeling and repair in health and disease. Trends Cell Biol2022; 32: 597–610.
25.
GoulCSZoncuR. PITTching in for lysosome repair. Dev Cell2022; 57: 2347–2349.
26.
TabataKSaekiMYoshimoriT, et al.How cells recognize and remove the perforated lysosome. Autophagy2023; 19: 1869–1871.
ZhuQGaoPToberJ, et al.Developmental trajectory of prehematopoietic stem cell formation from endothelium. Blood2020; 136: 845–856.
29.
LangeLMorganMSchambachA. The hemogenic endothelium: a critical source for the generation of PSC-derived hematopoietic stem and progenitor cells. Cell Mol Life Sci2021; 78: 4143–4160.
30.
MorimotoMNicoliERKuptanonC, et al.Spectrum of LYST mutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature. J Med Genet2024; 61: 212–223.
31.
García-PonceAChánez ParedesSCastro OchoaKF, et al.Regulation of endothelial and epithelial barrier functions by peptide hormones of the adrenomedullin family. Tissue Barriers2016; 4: e1228439.
32.
LuCHWeiSTLiuJJ, et al.Recognition of a novel gene signature for human glioblastoma. Int J Mol Sci2022; 23: 4157.
33.
LimSYAhnSHParkH, et al.Transcriptional regulation of adrenomedullin by oncostatin M in human astroglioma cells: implications for tumor invasion and migration. Sci Rep2014; 4: 6444.
34.
TobacmanJKBhattacharyyaS. Profound impact of decline in N-acetylgalactosamine-4-sulfatase (Arylsulfatase B) on molecular pathophysiology and human diseases. Int J Mol Sci2022; 23: 13146.
35.
ZhangXBhattacharyyaSKusumoH, et al.Arylsulfatase B modulates neurite outgrowth via astrocyte chondroitin-4-sulfate: dysregulation by ethanol. Glia2014; 62: 259–271.
36.
WeiYXiongZJLiJ, et al.Crystal structures of human lysosomal EPDR1 reveal homology with the superfamily of bacterial lipoprotein transporters. Commun Biol2019; 2: 52.
37.
LiaoYCFernandopulleMSWangG, et al.RNA Granules hitchhike on lysosomes for long-distance transport, using Annexin A11 as a molecular tether. Cell2019; 179: 147–164.e20.
38.
YasaSSauvageauEModicaG, et al.CLN5 And CLN3 function as a complex to regulate endolysosome function. Biochem J2021; 478: 2339–2357.
39.
LuebbenAVBenderDBeckerS, et al.Cln5 represents a new type of cysteine-based S-depalmitoylase linked to neurodegeneration. Sci Adv2022; 8: eabj8633.
40.
TangFLZhaoLZhaoY, et al.Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons. Cell Death Differ2020; 27: 2099–2116.
41.
DaiJLuYWangC, et al.Vps33b regulates Vwf-positive vesicular trafficking in megakaryocytes. J Pathol2016; 240: 108–119.
42.
LiuRJYAl-MoliehYChenSZ, et al.The Sec1-Munc18 protein VPS33B forms a uniquely bidirectional complex with VPS16B. J Biol Chem2023; 299: 104718.
43.
KelleyCMGinsbergSDAlldredMJ, et al.Maternal choline supplementation alters basal forebrain cholinergic neuron gene expression in the Ts65Dn mouse model of Down syndrome. Dev Neurobiol2019; 79: 664–683.
44.
NunoiHNakamuraHNishimuraT, et al.Recent topics and advanced therapies in chronic granulomatous disease. Hum Cell2023; 36: 515–527.
45.
BaiRShiZLiD, et al.Gene expression profile of human colorectal cancer identified NKTR as a biomarker for liver metastasis. Aging (Albany NY)2022; 14: 6656–6667.
46.
YeonGBShinWHYooSH, et al.NFIB Induces functional astrocytes from human pluripotent stem cell-derived neural precursor cells mimicking in vivo astrogliogenesis. J Cell Physiol2021; 236: 7625–7641.
47.
YangCWangHShaoM, et al.Brain-type glycogen phosphorylase (PYGB) in the pathologies of diseases: a systematic review. Cells2024; 13: 289.
48.
KimABXiaoQYanP, et al.Chimeric antigen receptor macrophages target and resorb amyloid plaques. JCI Insight2024; 9: e175015.
49.
CashmanJGhirmaiSAbelKJ, et al.Immune defects in Alzheimer's disease: new medications development. BMC Neurosci2008; 9: S13.
50.
KhanADasSSergiC. Therapeutic potential of neu1 in Alzheimer's disease via the immune system. Am J Alzheimers Dis Other Demen2021; 36: 1533317521996147.
51.
Podleśny-DrabiniokANovikovaGLiuY, et al.BHLHE40/41 Regulate microglia and peripheral macrophage responses associated with Alzheimer's disease and other disorders of lipid-rich tissues. Nat Commun2024; 15: 2058.
52.
MalongLNapoliICasalG, et al.Characterization of the structure and control of the blood-nerve barrier identifies avenues for therapeutic delivery. Dev Cell2023; 58: 174–191.e8.
53.
WangSShenHMaoQ, et al.Macrophage-mediated porous magnetic nanoparticles for multimodal imaging and postoperative photothermal therapy of gliomas. ACS Appl Mater Interfaces2021; 13: 56825–56837.
54.
WälchliTGhobrialMSchwabM, et al.Single-cell atlas of the human brain vasculature across development, adulthood and disease. Nature2024; 632: 603–613.
55.
ChoiTHYooRJParkJY, et al.Development of finely tuned liposome nanoplatform for macrophage depletion. J Nanobiotechnology2024; 22: 83.
56.
HastonSGonzalez-GualdaEMorsliS, et al.Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell2023; 41: 1242–1260.e6.
57.
RavichandranSManickamNKandasamyM. Liposome encapsulated clodronate mediated elimination of pathogenic macrophages and microglia: a promising pharmacological regime to defuse cytokine storm in COVID-19. Med Drug Discov2022; 15: 100136.
58.
LiSYGuoYLTianJW, et al.Anti-tumor strategies by harnessing the phagocytosis of macrophages. Cancers (Basel)2023; 15: 2717.
