Protein Aggregation Diseases: Mechanistic Insights and Therapeutic Strategies with a Focus on Alzheimer’s Disease
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Protein Aggregation Diseases: Mechanistic Insights and Therapeutic Strategies with a Focus on Alzheimer’s Disease

Xinyu Yang 1*
1 Sichuan University
*Corresponding author: 912345618@qq.com
Published on 28 October 2025
Journal Cover
TNS Vol.147
ISSN (Print): 2753-8826
ISSN (Online): 2753-8818
ISBN (Print): 978-1-80590-489-2
ISBN (Online): 978-1-80590-490-8
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Abstract

Proteins play a central role in regulating diverse cellular functions but remain stable only under specific physiological conditions. Even minor environmental changes can severely compromise their conformational stability, often leading to aggregation. Under normal circumstances, the cell’s quality control mechanisms efficiently remove or degrade these aggregated proteins. However, under pathological conditions, these protective systems may become overwhelmed or impaired, resulting in cellular toxicity. The misfolding of specific proteins and the formation of abnormal aggregates ultimately result in protein aggregation diseases, which share highly conserved molecular pathways in their pathogenesis. This review synthesizes the common molecular mechanisms underlying these diseases, with a particular focus on Alzheimer’s disease (AD) as a model system. By examining the specific pathology of AD, including the aggregation of amyloid β and Tau proteins, the review underscores AD’s dual role as both a primary example and a gateway for understanding related disorders. Furthermore, it outlines current clinical strategies and therapeutic approaches, emphasizing both universal and targeted interventions applicable to this class of diseases. By integrating multidisciplinary perspectives, this review aims to provide foundational insights and scientific reference points for future research and the development of more effective clinical therapies. The overarching goal is to deepen our understanding of protein aggregation diseases and to identify potential breakthroughs that could benefit a wide range of neurodegenerative disorders.

Keywords:

Protein Aggregation Diseases, Alzheimer’s Disease, Molecular Mechanisms, Amyloid β, Tau Protein.

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Yang,X. (2025). Protein Aggregation Diseases: Mechanistic Insights and Therapeutic Strategies with a Focus on Alzheimer’s Disease. Theoretical and Natural Science,147,45-54.

References

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[2]. Zheng, Q., and Wang, X. (2025) Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy. Protein & Cell, 16(2), 83-120.

[3]. Fan, T., Peng, J., Liang, H., Chen, W., Wang, J., and Xu, R. (2025) Potential common pathogenesis of several neurodegenerative diseases. Neural Regeneration Research, 21(3), 972-988.

[4]. Sun, K. T., and Mok, S. -A. (2025) Inducers and modulators of protein aggregation in Alzheimer’s disease - Critical tools for understanding the foundations of aggregate structures. Neurotherapeutics, 22(3), e00512.

[5]. Simon, P. Y. R., and David, R. (2025) Alzheimer’s Disease, β-Amyloid Peptides, and Ubiquitin-Proteasome System: Nutritherapeutic Insights. Neurodegenerative Disease, 25(2), 76-87.

[6]. Eid, S., Lee, S., Verkuyl, C. E., Almanza, D., Hanna, J., Shenouda, S., Belotserkovsky, A., Zhao, W., and Watts, J. C. (2024) The importance of prion research. Biochemistry and Cell Biology, 102(6), 448-471.

[7]. Aivalioti, E., Georgiopoulos, G., Tual-Chalot, S., Bampatsias, D., Delialis, D., Sopova, K., Drakos, S. G., Stellos, K., and Stamatelopoulos, K. (2025) Amyloid-beta metabolism in age-related neurocardiovascular diseases. European Heart Journal, 46(3), 250-272.

[8]. Ding, S., Choi, S. H., and Miller, Y. I. (2025) Amyloid β-Induced Inflammarafts in Alzheimer’s Disease. International Journal of Molecular Sciences, 26(10), 4592.

[9]. Zhang, X., Liu, Y., Rekowski, M. J., and Wang, N. (2025) Lactylation of tau in human Alzheimer’s disease brains. Alzheimer’s & Dementia, 21(2), e14481.

[10]. Kamatham, P. T., Shukla, R., Khatri, D. K., and Vora, L. K. (2024) Pathogenesis, diagnostics, and therapeutics for Alzheimer’s disease: Breaking the memory barrier. Ageing Research Reviews, 101, 102481.

[11]. Mishra, P., Esfahani, E. K., Fernyhough, P., and Albensi, B. C. (2025) Estradiol Prevents Amyloid Beta-Induced Mitochondrial Dysfunction and Neurotoxicity in Alzheimer’s Disease via AMPK-Dependent Suppression of NF-κB Signaling. International Journal of Molecular Sciences, 26(13), 6203.

[12]. Kadamangudi, S., Marcatti, M., Zhang, W. -R., Fracassi, A., Kayed, R., Limon, A., and Taglialatela, G. (2024) Amyloid-β oligomers increase the binding and internalization of tau oligomers in human synapses. Acta Neuropathologica, 149(1), 2.

[13]. Balducci, C., Orsini, F., Cerovic, M. et al. (2025) Tau oligomers impair memory and synaptic plasticity through the cellular prion protein. Acta Neuropathologica Communications, 13(1), 17.

[14]. Tiong, S. Q., Mohgan, R. N., Quek, J. Y., Liew, J. Y. S., Wong, G. Y. S., Thang, Z. Q., Chan, Z. L., Gan, S. Y., and Chan, E. W. L. (2025) Inhibition of the Transforming Growth Factor-β Signaling Pathway Confers Neuroprotective Effects on Beta-Amyloid-Induced Direct Neurotoxicity and Microglia-Mediated Neuroinflammation. Neurology Research International, 8948290.

[15]. Zhang, G., Peng, Q., Guo, X. et al. (2025) Microglia-derived Galectin-9 drives amyloid-β pathology in Alzheimer’s disease. Aging Cell, 24(2), e14396.

[16]. Wang, X., Wang, J., He, Y., Li, H., Yuan, H., Evans, A., Yu, X., He, Y., and Wang, H. (2015) Apolipoprotein E ε4 Modulates Cognitive Profiles, Hippocampal Volume, and Resting-State Functional Connectivity in Alzheimer’s Disease. Journal of Alzheimer’s Disease, 45(3), 781-95.

[17]. M, Y., and Shetty, N. S. (2025) Advances in the Synthetic Approaches to β‑Secretase (BACE-1) Inhibitors in Countering Alzheimer’s: A Comprehensive Review. ACS Omega, 10(32), 35367-35433.

[18]. Monteiro, K. L. C., Dos Santos Alcântara, M. G., Freire, N. M. L., Brandão, E. M., do Nascimento, V. L., Dos Santos Viana, L. M., de Aquino, T. M., and da Silva-Júnior, E. F. (2023) BACE-1 Inhibitors Targeting Alzheimer’s Disease. Current Alzheimer Research, 20(3), 131-148.

[19]. Melis, V., Magbagbeolu, M., Rickard, J. E. et al. (2015) Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models. Behav Pharmacol. 2015 Jun; 26(4): 353-68.

[20]. Wischik CM, Harrington CR, Storey JM. Tau-aggregation inhibitor therapy for Alzheimer's disease. Behavioural Pharmacology, 88(4), 529-39.

[21]. Duggal, A., Mahindru, D., Baghel, K., Mehrotra, S., and Prajapati, V. K. (2025) Tau protein aggregation: A therapeutic target for neurodegenerative diseases. Advances in Protein Chemistry and Structural Biology, 146, 77-136.

[22]. Jucker, M., and Walker, L. C. (2023) Alzheimer’s disease: From immunotherapy to immunoprevention. Cell, 186(20), 4260-4270.

[23]. Guo, X., Yan, L., Zhang, D., and Zhao, Y. (2024) Passive immunotherapy for Alzheimer’s disease. Ageing Research Reviews, 94, 102192.

[24]. Hampel, H., Elhage, A., Cho, M., Apostolova, L. G., Nicoll, J. A. R., and Atri, A. (2023) Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics. Brain, 146(11), 4414-4424.

[25]. Zhang, Z., Yang, X., Song, Y. Q., and Tu, J. (2021) Autophagy in Alzheimer's disease pathogenesis: Therapeutic potential and future perspectives. Ageing Research Reviews, 72, 101464.

[26]. Qin, Q., Teng, Z., Liu, C., Li, Q., Yin, Y., and Tang, Y. (2021) TREM2, microglia, and Alzheimer’s disease. Mechanisms of Ageing and Development, 195, 111438.

[27]. Zhao, X., Hu, Q., Wang, X. et al. (2024) Dual-target inhibitors based on acetylcholinesterase: Novel agents for Alzheimer's disease. European Journal of Medicinal Chemistry, 279, 116810.

[28]. Vemula, P., Schoch, K. M., and Miller, T. M. (2023) Evaluating the efficacy of purchased antisense oligonucleotides to reduce mouse and human tau in vivo. Frontiers in Molecular Neuroscience, 16, 1320182.

[29]. Cao, Z., Kong, F., Ding, J., Chen, C., He, F., and Deng, W. (2024) Promoting Alzheimer’s disease research and therapy with stem cell technology. Stem Cell Research & Therapy, 15(1), 136.

[30]. Wang, J., Jin, C., Zhou, J., Zhou, R., Tian, M., Lee, H. J., and Zhang, H. (2022) PET molecular imaging for pathophysiological visualization in Alzheimer’s disease. European Journal of Nuclear Medicine and Molecular Imaging, 50(3), 765-783.

References

[1]. Wu, J., Wu, J., Chen, T., Cai, J., and Ren, R. (2024) Protein aggregation and its affecting mechanisms in neurodegenerative diseases. Neurochemistry International, 180, 105880.

[2]. Zheng, Q., and Wang, X. (2025) Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy. Protein & Cell, 16(2), 83-120.

[3]. Fan, T., Peng, J., Liang, H., Chen, W., Wang, J., and Xu, R. (2025) Potential common pathogenesis of several neurodegenerative diseases. Neural Regeneration Research, 21(3), 972-988.

[4]. Sun, K. T., and Mok, S. -A. (2025) Inducers and modulators of protein aggregation in Alzheimer’s disease - Critical tools for understanding the foundations of aggregate structures. Neurotherapeutics, 22(3), e00512.

[5]. Simon, P. Y. R., and David, R. (2025) Alzheimer’s Disease, β-Amyloid Peptides, and Ubiquitin-Proteasome System: Nutritherapeutic Insights. Neurodegenerative Disease, 25(2), 76-87.

[6]. Eid, S., Lee, S., Verkuyl, C. E., Almanza, D., Hanna, J., Shenouda, S., Belotserkovsky, A., Zhao, W., and Watts, J. C. (2024) The importance of prion research. Biochemistry and Cell Biology, 102(6), 448-471.

[7]. Aivalioti, E., Georgiopoulos, G., Tual-Chalot, S., Bampatsias, D., Delialis, D., Sopova, K., Drakos, S. G., Stellos, K., and Stamatelopoulos, K. (2025) Amyloid-beta metabolism in age-related neurocardiovascular diseases. European Heart Journal, 46(3), 250-272.

[8]. Ding, S., Choi, S. H., and Miller, Y. I. (2025) Amyloid β-Induced Inflammarafts in Alzheimer’s Disease. International Journal of Molecular Sciences, 26(10), 4592.

[9]. Zhang, X., Liu, Y., Rekowski, M. J., and Wang, N. (2025) Lactylation of tau in human Alzheimer’s disease brains. Alzheimer’s & Dementia, 21(2), e14481.

[10]. Kamatham, P. T., Shukla, R., Khatri, D. K., and Vora, L. K. (2024) Pathogenesis, diagnostics, and therapeutics for Alzheimer’s disease: Breaking the memory barrier. Ageing Research Reviews, 101, 102481.

[11]. Mishra, P., Esfahani, E. K., Fernyhough, P., and Albensi, B. C. (2025) Estradiol Prevents Amyloid Beta-Induced Mitochondrial Dysfunction and Neurotoxicity in Alzheimer’s Disease via AMPK-Dependent Suppression of NF-κB Signaling. International Journal of Molecular Sciences, 26(13), 6203.

[12]. Kadamangudi, S., Marcatti, M., Zhang, W. -R., Fracassi, A., Kayed, R., Limon, A., and Taglialatela, G. (2024) Amyloid-β oligomers increase the binding and internalization of tau oligomers in human synapses. Acta Neuropathologica, 149(1), 2.

[13]. Balducci, C., Orsini, F., Cerovic, M. et al. (2025) Tau oligomers impair memory and synaptic plasticity through the cellular prion protein. Acta Neuropathologica Communications, 13(1), 17.

[14]. Tiong, S. Q., Mohgan, R. N., Quek, J. Y., Liew, J. Y. S., Wong, G. Y. S., Thang, Z. Q., Chan, Z. L., Gan, S. Y., and Chan, E. W. L. (2025) Inhibition of the Transforming Growth Factor-β Signaling Pathway Confers Neuroprotective Effects on Beta-Amyloid-Induced Direct Neurotoxicity and Microglia-Mediated Neuroinflammation. Neurology Research International, 8948290.

[15]. Zhang, G., Peng, Q., Guo, X. et al. (2025) Microglia-derived Galectin-9 drives amyloid-β pathology in Alzheimer’s disease. Aging Cell, 24(2), e14396.

[16]. Wang, X., Wang, J., He, Y., Li, H., Yuan, H., Evans, A., Yu, X., He, Y., and Wang, H. (2015) Apolipoprotein E ε4 Modulates Cognitive Profiles, Hippocampal Volume, and Resting-State Functional Connectivity in Alzheimer’s Disease. Journal of Alzheimer’s Disease, 45(3), 781-95.

[17]. M, Y., and Shetty, N. S. (2025) Advances in the Synthetic Approaches to β‑Secretase (BACE-1) Inhibitors in Countering Alzheimer’s: A Comprehensive Review. ACS Omega, 10(32), 35367-35433.

[18]. Monteiro, K. L. C., Dos Santos Alcântara, M. G., Freire, N. M. L., Brandão, E. M., do Nascimento, V. L., Dos Santos Viana, L. M., de Aquino, T. M., and da Silva-Júnior, E. F. (2023) BACE-1 Inhibitors Targeting Alzheimer’s Disease. Current Alzheimer Research, 20(3), 131-148.

[19]. Melis, V., Magbagbeolu, M., Rickard, J. E. et al. (2015) Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models. Behav Pharmacol. 2015 Jun; 26(4): 353-68.

[20]. Wischik CM, Harrington CR, Storey JM. Tau-aggregation inhibitor therapy for Alzheimer's disease. Behavioural Pharmacology, 88(4), 529-39.

[21]. Duggal, A., Mahindru, D., Baghel, K., Mehrotra, S., and Prajapati, V. K. (2025) Tau protein aggregation: A therapeutic target for neurodegenerative diseases. Advances in Protein Chemistry and Structural Biology, 146, 77-136.

[22]. Jucker, M., and Walker, L. C. (2023) Alzheimer’s disease: From immunotherapy to immunoprevention. Cell, 186(20), 4260-4270.

[23]. Guo, X., Yan, L., Zhang, D., and Zhao, Y. (2024) Passive immunotherapy for Alzheimer’s disease. Ageing Research Reviews, 94, 102192.

[24]. Hampel, H., Elhage, A., Cho, M., Apostolova, L. G., Nicoll, J. A. R., and Atri, A. (2023) Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics. Brain, 146(11), 4414-4424.

[25]. Zhang, Z., Yang, X., Song, Y. Q., and Tu, J. (2021) Autophagy in Alzheimer's disease pathogenesis: Therapeutic potential and future perspectives. Ageing Research Reviews, 72, 101464.

[26]. Qin, Q., Teng, Z., Liu, C., Li, Q., Yin, Y., and Tang, Y. (2021) TREM2, microglia, and Alzheimer’s disease. Mechanisms of Ageing and Development, 195, 111438.

[27]. Zhao, X., Hu, Q., Wang, X. et al. (2024) Dual-target inhibitors based on acetylcholinesterase: Novel agents for Alzheimer's disease. European Journal of Medicinal Chemistry, 279, 116810.

[28]. Vemula, P., Schoch, K. M., and Miller, T. M. (2023) Evaluating the efficacy of purchased antisense oligonucleotides to reduce mouse and human tau in vivo. Frontiers in Molecular Neuroscience, 16, 1320182.

[29]. Cao, Z., Kong, F., Ding, J., Chen, C., He, F., and Deng, W. (2024) Promoting Alzheimer’s disease research and therapy with stem cell technology. Stem Cell Research & Therapy, 15(1), 136.

[30]. Wang, J., Jin, C., Zhou, J., Zhou, R., Tian, M., Lee, H. J., and Zhang, H. (2022) PET molecular imaging for pathophysiological visualization in Alzheimer’s disease. European Journal of Nuclear Medicine and Molecular Imaging, 50(3), 765-783.

Cite this article

Yang,X. (2025). Protein Aggregation Diseases: Mechanistic Insights and Therapeutic Strategies with a Focus on Alzheimer’s Disease. Theoretical and Natural Science,147,45-54.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

About volume

Volume title: Proceedings of ICBioMed 2025 Symposium: AI for Healthcare: Advanced Medical Data Analytics and Smart Rehabilitation

ISBN: 978-1-80590-489-2(Print) / 978-1-80590-490-8(Online)
Editor: Alan Wang
Conference website: https://2025.icbiomed.org/auckland.html
Conference date: 17 October 2025
Series: Theoretical and Natural Science
Volume number: Vol.147
ISSN: 2753-8818(Print) / 2753-8826(Online)

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