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Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease
Open accessAbstract
Extracellular neuritic plaques composed of amyloid‑β (Aβ) protein and intracellular neurofibrillary tangles containing phosphorylated tau protein are the two hallmark proteins of Alzheimer's disease (AD), and the separate neurotoxicity of these proteins in AD has been extensively studied. However, interventions that target Aβ or tau individually have not yielded substantial breakthroughs. The interest in the interactions between Aβ and tau in AD is increasing, but related drug investigations are in their infancy. This review discusses how Aβ accelerates tau phosphorylation and the possible mechanisms and pathways by which tau mediates Aβ toxicity. This review also describes the possible synergistic effects between Aβ and tau on microglial cells and astrocytes. Studies suggest that the coexistence of Aβ plaques and phosphorylated tau is related to the mechanism by which Aβ facilitates the propagation of tau aggregation in neuritic plaques. The interactions between Aβ and tau mediate cognitive dysfunction in patients with AD. In summary, this review summarizes recent data on the interplay between Aβ and tau to promote a better understanding of the roles of these proteins in the pathological process of AD and provide new insights into interventions against AD.
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“For instance, Aβ oligomers promote tau phosphorylation and mislocalization by activating kinases such as GSK-3, CDK5, and Fyn kinase, and by interfering with tau degradation [50].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [50]
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“Through the cellular prion protein/mGluR5 complex, Aβ oligomers can trigger Fyn kinase activation, further driving tau toxicity [50].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [50]
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“Since amyloid-beta (Aβ) plaques and tau tangles are characteristic of AD and are thought to be important in the onset and development of the disease, the main focus of these therapies has been on removing or reducing them.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [84]
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“The two toxic protein compounds, A β and Tau, come into action at different temporal stages of the disease showing different degrees of harmfulness [15,16].”
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Dual impact of neuroinflammation on cognitive and motor impairments in Alzheimer's disease
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Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review
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“Abnormal aggregation of tau is a central pathogenic mechanism in Alzheimer’s disease (AD) and related disorders (Zhang et al., 2021).”
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A new perspective on Alzheimer’s disease: m6A modification
Xia, L., Zhang, F., Li, Y., Mo, Y., Zhang, L., Li, Q., Luo, M., Hou, X., Du, Z., Deng, J., et al. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1166831 · Cited by 32
Nanomedicine-based immunotherapy for Alzheimer's disease
Hoque, M., Samanta, A., Alam, S. S. M., Zughaibi, T. A., Kamal, M. A., & Tabrez, S. S. M. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104973 · Cited by 31
Common Signaling Pathways Involved in Alzheimer’s Disease and Stroke: Two Faces of the Same Coin
Das, T. K., Ganesh, B. P., & Fatima-Shad, K. (2023) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-220108 · Cited by 33
Unveiling the Therapeutic Potentials of Mushroom Bioactive Compounds in Alzheimer’s Disease
Li, N., Li, H., Liu, Z., Feng, G., Shi, C., & Wu, Y. (2023) · Foods · doi:10.3390/foods12152972 · Cited by 34
“Research indicated that the development of AD is related to a variety of factors, such as Aβ deposition and tau protein aggregation [3].”
BackgroundpH regulating mechanisms of astrocytes: A critical component in physiology and disease of the brain
Theparambil, S. M., Begum, G., & Rose, C. R. (2024) · Cell Calcium · doi:10.1016/j.ceca.2024.102882 · Cited by 31
Al-Kuraishy, H. M., Sulaiman, G. M., Mohammed, H. A., Dawood, R. A., Albuhadily, A. K., Al-Gareeb, A. I., Abomughaid, M. M., & Klionsky, D. J. (2025) · Neuropsychopharmacology Reports · doi:10.1002/npr2.12525 · Cited by 31
Retinal Alterations Predict Early Prodromal Signs of Neurodegenerative Disease
Casciano, F., Zauli, E., Celeghini, C., Caruso, L., Gonelli, A., Zauli, G., & Pignatelli, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031689 · Cited by 34
“Although the accumulation of insoluble A β is recognized as a factor in the pathogenesis of AD, tau aggregation and neuroinflammation by damaging neuronal cells also play a role in AD development [130].”
BackgroundSamsuzzaman, M., Lee, J. H., Hong, S., Park, H., Chang, K., Kim, H.-B., Park, M. G., Eo, H., Oh, M. S., & Kim, S. Y. (2024) · Biological Research · doi:10.1186/s40659-024-00572-4 · Cited by 34
“Tau phosphorylation and oAβ deposition have been associated with rapid cognitive decline, and the Akt/ GSK-3β (Ser9) signaling axis acts as an upstream regulator [45].”
Protein aggregation in neurodegenerative diseases
Wang, J., Dai, L., & Zhang, Z. (2025) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003802 · Cited by 29
Protective effect of flavonoids on oxidative stress injury in Alzheimer’s disease
Wang, K., & Chen, X. (2024) · Natural Product Research · doi:10.1080/14786419.2024.2345760 · Cited by 30
“Dysregulation of protein kinases such as cyclin-dependent kinase-5 (CDK-5) and glycogen synthase kinase-3β (GsK-3β) can cause hyperphosphorylation of Tau protein and produce neurotoxicity (Wegmann et al. 2021; Zhang et al. 2021).”
Alzheimer disease: Amyloid peptide controversies and challenges of anti-Aβ immunotherapy
Almohmadi, N. H., Al-Kuraishy, H. M., Albuhadily, A. K., Al-Gareeb, A. I., Abdelaziz, A. M., Alexiou, A. T., Papadakis, M., & Batiha, G. E. (2025) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/j.jpet.2025.103639 · Cited by 29
“18 The results re-ported here indicate a mutual association between A ß and hyperphosphorylated tau protein in the etiology of AD and the neurodegeneration of cholinergic neurons.”
InfluentialPradeepkiran, J. A., Munikumar, M., Reddy, A. P., & Reddy, P. H. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab244 · Cited by 28
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Jain, S. K., Stevens, C. M., Margret, J. J., & Levine, S. N. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2023.0245 · Cited by 33
“…that GSH can protect against neuronal damage by different mechanisms, including activation of nerve growth factor, glial cell-derived neurotrophic factor, nitric oxide synthase, and choline acetyl transferase (Haddad et al., 2021; Iskusnykh et al., 2022; Nakamura et al., 2021; Zhang et al., 2021b).”
Natural Compounds for Preventing Age-Related Diseases and Cancers
Ki, M., Youn, S., Kim, D. H., & Pack, S. P. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147530 · Cited by 30
The complex effects of miR-146a in the pathogenesis of Alzheimer’s disease
Long, Y., Liu, J., Wang, Y., Guo, H.-D., & Cui, G.-H. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01566 · Cited by 34
Brezić, N., Gligorevic, S., Sič, A., & Knežević, N. N. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47040259 · Cited by 31
“A β and tau pathologies synergize: A β aggregates can seed tau misfolding in a prion-like manner, exacerbating neurotoxicity in AD [59].”
Alzheimer’s Disease Etiology Hypotheses and Therapeutic Strategies: A Perspective
Scarano, N., Musumeci, F., Casini, B., Brullo, C., D’Ursi, P., Fossa, P., Schenone, S., & Cichero, E. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26146980 · Cited by 32
“However, other studies highlight the mutual influence between Tau and A β mechanisms, hypothesizing a synergistic effect between the two processes [209,210].”
Alzheimer’s Disease: From Molecular Mechanisms to Promising Therapeutic Strategies
Ivanova, A. V., Kutuzova, A. D., Kuzmichev, I., & Abakumov, M. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199444 · Cited by 33
Associations of Blood and Cerebrospinal Fluid Aβ and tau Levels with Renal Function
Sun, H., Yao, X., Li, L., Jin, W., Bai, Y., Zeng, G., Shi, A., Liang, J., Zhu, L., Liu, Y.-H., et al. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03420-w · Cited by 27
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Exploring Alzheimer's disease treatment: Established therapies and novel strategies for future care
Soni, U., Singh, K., Jain, D., & Pujari, R. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.177520 · Cited by 28
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“Mild Demented scans show subtle cortical thinning and hippocampal atrophy [58], while Non-Demented scans exhibit preserved structures [7].”
Okafor, M., Gonzalez, P., Ronot, P., Masoudi, I. E., Boos, A., Ory, S., Chasserot‐Golaz, S., Gasman, S., Raibaut, L., Hureau, C., et al. (2022) · Chemical Science · doi:10.1039/d2sc02593k · Cited by 27
Neuronal plasticity and its role in Alzheimer’s disease and Parkinson’s disease
Jahan, I., Harun‐Ur‐Rashid, M., Islam, M. A., Sharmin, F., Jaouni, S. K. A., Kaki, A. M., & Selim, S. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-01019 · Cited by 31
“Pathophysiology and impact on plasticity Amyloid-beta plaques and their effects on neuronal plasticity AD is a progressive neurodegenerative disorder characterized by the presence of Aβ plaques and tau tangles, which significantly impact neuronal plasticity (Zhang et al., 2021).”
Rahman, M. A., Khatun, M. T., Mim, A. K., Khandocar, M. P., Rahman, A., Hasan, M. H., Shimki, A. I., Hossain, M. S., Shoily, M. S. A., Faraque, A., et al. (2025) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-025-01845-9 · Cited by 27
“Speci fi c locations are phosphorylated by kinases such as CDK-5 and GSK-3 β , although tau aggregation and NFTs are caused by pathological hyper-activity [94].”
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Application of Optogenetics in Neurodegenerative Diseases
Zhang, Q., Li, T., Xu, M., Islam, B., & Wang, J. (2024) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-024-01486-1 · Cited by 25
“This impairs the transport system of neurons, affecting cell health and function and thereby advancing neurodegeneration (Zhang et al. 2021).”
BackgroundA multi-targeting immunotherapy ameliorates multiple facets of Alzheimer’s disease in 3xTg mice
Feng, X., Hou, Y., Liu, J., Yan, F., Dai, M., Chen, M., Wang, J., Li, J., Liu, Z., Sun, D., et al. (2024) · npj Vaccines · doi:10.1038/s41541-024-00942-9 · Cited by 28
Metadata
- Authors
- Zhang, H., Wei, W., Zhao, M., Ma, L., Jiang, X., Pei, H., Cao, Y., & Li, H.
- Affiliations
- Xiyuan Hospital (CN)
- Beijing University of Chinese Medicine (CN)
- Corresponding author
- Cao, Yu
- Li, Hao
- Venue
- International Journal of Biological Sciences
- Publisher
- Ivyspring International Publisher
- Published
- 2021
- Volume
- 17
- Issue
- 9
- Pages
- 2181-2192
- ISSN
- 1449-2288 (ISSN-L)
- PMC
- PMC8241728
- OpenAlex
- W3166313369
- Cited by
- 689
- References
- 185
- Citations by year
- 2026: 182 · 2025: 268 · 2024: 141 · 2023: 73 · 2022: 22 · 2021: 3
- FWCI
- 37.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- International Journal of Biological Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81873350, 7202174)
- National Science and Technology Major Project
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta, tau protein, tau phosphorylation, neuritic plaques, neurofibrillary tangles, microglia, astrocytes, tau aggregation, cognitive impairment, neurotoxicity
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Humans, Phosphorylation, Amyloid beta-Peptides, tau Proteins
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