阿尔茨海默病中增强和恢复溶酶体功能的途径研究进展

doi:10.3969/j.issn.1003-9198.2026.02.015

Abstract

Abstract: Lysosomal dysfunction is an important part of the pathological mechanism of Alzheimer’s disease, and its functional repair provides a new opportunity for disease intervention. This paper systematically reviews six major strategies for restoring lysosomal function: activation and regulation of transcription factor EB, modulation of the autophagy-lysosome pathway, traditional Chinese medicine interventions, exercise therapy, application of nanomaterials, and the development of novel lysosomal enhancers. It also provides an in-depth discussion of the molecular mechanisms, model validation, and clinical translation potential. By integrating basic research and advances in translational medicine, this review aims to provide a theoretical basis and innovative direction for Alzheimer’s disease therapy.

Key words: Alzheimer’s disease, lysosome, transcription factor EB, autophagy, traditional Chinese medicine, nanotechnology

CLC Number:

R 749.16

YANG Xin, SHI Shengliang. Research progress on the pathways of enhancing and restoring lysosomal function in Alzheimer’s disease[J]. Practical Geriatrics, 2026, 40(2): 180-184.

References

[1] NIXON R A, RUBINSZTEIN D C. Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases[J]. Nat Rev Mol Cell Biol, 2024, 25(11): 926-946.
[2] CHEN M, DAI Y, LIU S, et al. TFEB biology and agonists at a glance[J]. Cells, 2021, 10(2): 333.
[3] ABOKYI S, GHARTEY-KWANSAH G, TSE D Y. TFEB is a central regulator of the aging process and age-related diseases[J]. Ageing Res Rev, 2023, 89: 101985.
[4] NAH J, SUNG E A, ZHAI P, et al. Tfeb-mediated transcriptional regulation of autophagy induces autosis during ischemia/reperfusion in the heart[J]. Cells, 2022, 11(2): 258.
[5] TAKLA M, KESHRI S, RUBINSZTEIN D C. The post-translational regulation of transcription factor EB (TFEB) in health and disease[J]. EMBO Rep, 2023, 24(11): e57574.
[6] WANG B, MARTINI-STOICA H, QI C, et al. TFEB-vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy[J]. Nat Neurosci, 2024, 27(1): 48-62.
[7] ZHANG Y D, ZHAO J J. TFEB participates in the Aβ-induced pathogenesis of Alzheimer’s disease by regulating the autophagy-lysosome pathway[J]. DNA Cell Biol, 2015, 34(11): 661-668.
[8] XU Y, WANG Q, WANG J, et al. The cGAS-STING pathway activates transcription factor TFEB to stimulate lysosome biogenesis and pathogen clearance[J]. Immunity, 2025, 58(2): 309-325.e6.
[9] YANG C, SU C, IYASWAMY A, et al.Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates Tau pathology: implications for Alzheimer’s disease therapy[J]. Acta Pharm Sin B, 2022, 12(4): 1707-1722.
[10] LI T, YIN L, KANG X, et al. TFEB acetylation promotes lysosome biogenesis and ameliorates Alzheimer’s disease-relevant phenotypes in mice[J]. J Biol Chem, 2022, 298(12): 102649.
[11] WANG Y, HUANG Y, LIU J, et al. Acetyltransferase GCN5 regulates autophagy and lysosome biogenesis by targeting TFEB[J]. EMBO Rep, 2020, 21(1): e48335.
[12] WANG X, XIE Y, CHEN G, et al. Intermittent hypoxia therapy ameliorates beta-amyloid pathology via TFEB-mediated autophagy in murine Alzheimer’s disease[J]. J Neuroinflammation, 2023, 20(1): 240.
[13] ZHANG Z, YANG X, SONG Y Q, et al.Autophagy in Alzheimer’s disease pathogenesis: therapeutic potential and future perspectives[J]. Ageing Res Rev, 2021, 72: 101464.
[14] WANG J, LIU B, XU Y, et al. Activation of CREB-mediate dautophagy by thioperamide ameliorates β-amyloid pathology and cognition in Alzheimer’s disease[J]. Aging Cell, 2021, 20(3): e13333.
[15] NIXON R A. Autophagy-lysosomal-associated neuronal death in neurodegenerative disease[J]. Acta Neuropathol, 2024, 148(1): 42.
[16] TONG B C, HUANG A S, WU A J, et al.Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies[J]. J Biomed Sci, 2022, 29(1): 85.
[17] KIM S, KIM D K, JEONG S, et al. The common cellular events in the neurodegenerative diseases and the associated role of endoplasmic reticulum stress[J]. Int J Mol Sci, 2022, 23(11): 5894.
[18] LI S, WU Z, LE W. Traditional Chinese medicine for dementia[J]. Alzheimers Dement, 2021, 17(6): 1066-1071.
[19] JIE K, CAIYI S, XIN L. Etiology and pathogenesis of Alzheimers disease based on the theory of traditional Chinese medicine[J]. J Biomed Res Environ Sci, 2022, 3(12): 1413-1417.
[20] LI S, YANG J. Pathogenesis of Alzheimer’s disease and therapeutic strategies involving traditional Chinese medicine[J]. RSC Med Chem, 2024, 15(12): 3950-3969.
[21] IYASWAMY A, KRISHNAMOORTHI S K, ZHANG H, et al.Qingyangshen mitigates amyloid-β and Tau aggregate defects involving PPARα-TFEB activation in transgenic mice of Alzheimer’s disease[J]. Phytomedicine, 2021, 91: 153648.
[22] YIN P, WANG H, XUE T, et al. Four-dimensional label-free quantitative proteomics of ginsenoside Rg₂ ameliorated scopolamine-induced memory impairment in mice through the lysosomal pathway[J]. J Agric Food Chem, 2024, 72(26): 14640-14652.
[23] ZENG P, SU H F, YE C Y, et al. A tau pathogenesis-based network pharmacology approach for exploring the protections of Chuanxiong rhizoma in Alzheimer’s disease[J]. Front Pharmacol, 2022, 13: 877806.
[24] ZHAO Y, LONG Z, DING Y, et al. Dihydroartemisinin ameliorates learning and memory in Alzheimer’s disease through promoting autophagosome-lysosome fusion and autolysosomal degradation for Aβ clearance[J]. Front Aging Neurosci, 2020, 12: 47.
[25] 栗晨璐, 杨晓坤, 高誉珊, 等.基于内体-溶酶体系统探讨电针“百会”“涌泉”改善APP/PS1双转基因小鼠学习记忆能力的作用机制[J].针刺研究, 2023, 48(8):791-798.
[26] CARDONA M I, AFI A, LAKICEVIC N, et al. Physical activity interventions and their effects on cognitive function in people with dementia: a systematic review and meta-analysis[J]. Int J Environ Res Public Health, 2021, 18(16): 8753.
[27] YUEDE C M, TIMSON B F, HETTINGER J C, et al. Interactions between stress and physical activity on Alzheimer’s disease pathology[J]. Neurobiol Stress, 2018, 8: 158-171.
[28] DE LA ROSA A, OLASO-GONZALEZ G, ARC-CHAGNAUD C, et al. Physical exercise in the prevention and treatment of Alzheimer’s disease[J]. J Sport Health Sci, 2020, 9(5): 394-404.
[29] HUANG X, ZHAO X, LI B, et al. Comparative efficacy of various exercise interventions on cognitive function in patients with mild cognitive impairment or dementia:a systematic review and network meta-analysis[J]. J Sport Health Sci, 2022, 11(2): 212-223.
[30] 贾俊, 周迎松, 楼琼, 等. 运动调控自噬溶酶体通路改善阿尔茨海默病的机制[J]. 生物化学与生物物理进展, 2023, 50(10): 2314-2324.
[31] JIAN Y, YUAN S, YANG J, et al. Aerobicexercise alleviates abnormal autophagy in brain cells of APP/PS1 mice by upregulating AdipoR1 levels[J]. Int J Mol Sci, 2022, 23(17): 9921.
[32] WU J J, YU H, BI S G, et al. Aerobic exercise attenuatesautophagy-lysosomal flux deficits by ADRB2/β2-adrenergic receptor-mediated V-ATPase assembly factor VMA21 signaling in APP-PSEN1/PS1 mice[J]. Autophagy, 2024, 20(5): 1015-1031.
[33] ZHAO N, ZHANG X, SONG C, et al. The effects of treadmill exercise on autophagy in hippocampus of APP/PS1 transgenic mice[J]. Neuroreport, 2018, 29(10): 819-825.
[34] WANG X, ZHU Y T, ZHU Y, et al. Long-term running exercise alleviates cognitive dysfunction in APP/PSEN1 transgenic mice via enhancing brain lysosomal function[J]. Acta Pharmacol Sin, 2022, 43(4): 850-861.
[35] YIN T, LIU Y, HE B, et al. Cell primitive-basedbiomimetic nanomaterials for Alzheimer’s disease targeting and therapy[J]. Mater Today Bio, 2023, 22: 100789.
[36] FAN Z, REN T, WANG Y, et al. Aβ-responsive metform in-based supramolecular synergistic nanodrugs for Alzheimer’s disease via enhancing microglial Aβ clearance[J]. Biomaterials, 2022, 283: 121452.
[37] RATHORE B, SUNWOO K, JANGILI P, et al.Nanomaterial designing strategies related to cell lysosome and their biomedical applications: a review[J]. Biomaterials, 2019, 211: 25-47.
[38] KANAZIRSKA M V, FUCHS P M, CHEN L, et al. Beneficial effects of lysosome-modulating and other pharmacological and nanocarrier agents on amyloid-beta-treated cells[J]. Curr Pharm Biotechnol, 2012, 13(15): 2761-2767.
[39] HAO M, CHU J, ZHANG T, et al.Nanomaterials-mediated lysosomal regulation: a robust protein-clearance approach for the treatment of Alzheimer’s disease[J]. Neural Regen Res, 2025, 20(2): 424-439.
[40] WU Q, KARTHIVASHAN G, NAKHAEI-NEJAD M, et al. Native PLGA nanoparticles regulate APP metabolism and protect neurons against β-amyloid toxicity: potential significance in Alzheimer’s disease pathology[J]. Int J Biol Macromol, 2022, 219: 1180-1196.
[41] FENG Y, FU H, ZHANG X, et al. Lysosome toxicities induced by nanoparticle exposure and related mechanisms[J]. Ecotoxicol Environ Saf, 2024, 286: 117215.
[42] VEST R T, CHOU C C, ZHANG H, et al. Small molecule C381 targets thelysosome to reduce inflammation and ameliorate disease in models of neurodegeneration[J]. Proc Natl Acad Sci USA, 2022, 119(11): e2121609119.
[43] ZHOU J, WANG N, WANG M, et al. Discovery and optimization of tetrahydroisoquinoline derivatives to enhance lysosome biogenesis as preclinical candidates for the treatment of Alzheimer’s disease[J]. J Med Chem, 2024, 67(11): 8836-8861.

Research progress on the pathways of enhancing and restoring lysosomal function in Alzheimer’s disease

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 15

Metrics

Recommended 10

[1]	SUN Yang, GUO Ying. Research progress on drug targets for Alzheimer’s disease-related cognitive impairment [J]. Practical Geriatrics, 2026, 40(2): 116-120.
[2]	CHENG Yi, ZOU Ting, LI Lihua, ZHANG Lei, ZHOU Xiaohui. Study on the mechanism of lncRNA AL133415.1 in regulating vimentin gene expression in SH-SY5Y cells [J]. Practical Geriatrics, 2026, 40(2): 126-131.
[3]	LUO Jing, ZHANG Yufeng, GAO Xiaolong, GU Guojun. Application of amide proton transfer magnetic resonance imaging in early diagnosis of Alzheimer’s disease [J]. Practical Geriatrics, 2026, 40(2): 164-168.
[4]	WANG Miaohui, FAN Xuhang, CHEN Siyao, YANG Xiaojuan. Research progress on the correlation between Alzheimer’s disease and osteoporosis [J]. Practical Geriatrics, 2025, 39(9): 937-941.
[5]	YANG Huijuan, LIU Shunying, SU Jing, ZENG Liting. Advances in the application of artificial intelligence in the full-course management of Alzheimer’s disease [J]. Practical Geriatrics, 2025, 39(8): 768-772.
[6]	ZHONG Yi, FENG Yue, ZHANG Xinlong, DING Rui, SI Yanna. Research progress in single-cell RNA sequencing for Alzheimer’s disease [J]. Practical Geriatrics, 2025, 39(8): 857-861.
[7]	GU Xingyue, GAO Wei, LU Xiang. Advances in the study of enzymatic protein glycosylation in Alzheimer’s disease [J]. Practical Geriatrics, 2025, 39(6): 631-635.
[8]	WANG Yun, FU Liping. Significance of retinal structural and functional changes in the diagnosis of Alzheimer’s disease in high-altitude regions [J]. Practical Geriatrics, 2025, 39(5): 461-465.
[9]	WANG Yan, XU Jie, GU Xiaoping. Research advances on association between fatty acid metabolism and Alzheimer’s disease [J]. Practical Geriatrics, 2025, 39(4): 415-419.
[10]	LIN Xiaoqi, ZHAO Xinjing, WU Yashuang, ZHAO Wei, CHEN Chen, GAO Tianyu, ZHOU Guoyu. Advances of the mechanisms of gender differences in Alzheimer’s disease [J]. Practical Geriatrics, 2025, 39(4): 420-425.
[11]	CHEN Pengyao, ZHAO Ziwei, ZHAN Xianghong, LIU Yong. Role of insulin resistance in different brain regions in Alzheimer’s disease [J]. Practical Geriatrics, 2025, 39(11): 1163-1168.
[12]	YUAN Lili, ZOU Qiangwei. Advances in multi-omics research on Alzheimer’s disease [J]. Practical Geriatrics, 2025, 39(10): 1003-1008.
[13]	HU Yangyang, WANG Yue, XIE Qinglei. Effects of traditional Chinese medicine constitution dialectical nursing on fatigue and quality of life in elderly patients receiving dialysis [J]. Practical Geriatrics, 2024, 38(6): 545-548.
[14]	LI Qingyang, WANG Chanjuan, WANG Zheng. Study on the correlation of cognitive function with swallowing function and nutritional status in the elderly patients with Alzheimer’s disease [J]. Practical Geriatrics, 2024, 38(6): 577-581.
[15]	LIU Tian, YANG Rongli, HAN Huiping. Value of serum levels of Aβ1-42 and Bcl-2 in predicting the pathogenesis of Alzheimer’s disease in elderly patients with cognitive impairment [J]. Practical Geriatrics, 2024, 38(6): 582-586.