Neural Plasticity in Neurodegeneration: Exploring Adaptive and Maladaptive Mechanisms for Therapeutic Advances

Year 2025, Volume: 32 Issue: 3, 248 - 264, 09.09.2025

Ahmet Alperen Palabıyık

Abstract

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's, represent a significant challenge for modern medicine, marked by progressive neuronal dysfunction and loss. Emerging evidence highlights the critical role of neuroplasticity, the brain's ability to reorganize and adapt in response to damage, in mitigating cognitive and functional decline in these diseases. This review examines the molecular mechanisms underlying synaptic plasticity, with a focus on the interaction between neuroinflammation and plasticity in neurodegenerative conditions. We explore various therapeutic strategies, including pharmacological interventions, non-pharmacological approaches like physical exercise and cognitive training, and advanced technologies such as brain-computer interfaces (BCIs) and neuroimaging techniques. High-efficiency omics technologies, including genomics, proteomics, and metabolomics, have provided valuable insights into the genetic, molecular, and biochemical factors that influence synaptic function and plasticity. Additionally, immune modulation, through pharmacological and cellular therapies, offers a promising avenue for enhancing neuroplasticity. This review also emphasizes the integration of multimodal strategies, combining pharmacological treatments with advanced neurorehabilitation techniques. By understanding the intricate molecular networks that govern plasticity, researchers can develop more targeted and personalized therapies, aiming to preserve brain function and slow disease progression in individuals with neurodegenerative diseases.

Keywords

Neuroplasticity , neurodegenerative diseases , synaptic plasticity , therapeutic strategies , brain-computer interfaces (BCIS)

Ethical Statement

Not applicable.

Supporting Institution

Not applicable.

Project Number

Not applicable.

Thanks

Not applicable.

References

• 1. Savelieff MG, Nam G, Kang J, Lee HJ, et al. Development of multifunctional molecules as potential therapeutic candidates for Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis in the last decade. Chemical Reviews 2018;119(2),1221-1322.
• 2. Amartumur S, Nguyen H, Huynh T, et al. Neuropathogenesis-on-chips for neurodegenerative diseases. Nat Commun 2024;15,2219.
• 3. Muddapu VR, Dharshini SAP, Chakravarthy VS, et al. Neurodegenerative diseases: Is metabolic deficiency the root cause? Front Neurosci 2020;14:213.
• 4. Mateos-Aparicio P, Rodríguez-Moreno A. The impact of studying brain plasticity. Front Cell Neurosci 2019;13:66.
• 5. Milbocker KA, Smith IF, Klintsova AY. Maintaining a dynamic brain: A review of empirical findings describing the roles of exercise, learning, and environmental enrichment in neuroplasticity from 2017-2023. Brain Plasticity 2024;1-21.
• 6. Park J, Lee K, Kim K, et al. The role of histone modifications: From neurodevelopment to neurodiseases. Sig Transduct Target Ther 2022;7,217.
• 7. Dorszewska J, Kozubski W, Waleszczyk W, et al. Neuroplasticity in the pathology of neurodegenerative diseases. Neural Plasticity 2020;4245821.
• 8. Wang J, Chen S, Pan C, Li G, et al. Application of small molecules in the central nervous system direct neuronal reprogramming. Front. Bioeng Biotechnol 2022;10:799152.
• 9. Chu HY. Synaptic and cellular plasticity in Parkinson’s disease. Acta Pharmacol Sin 2020;41,447–452.
• 10. Teleanu RI, Niculescu A-G, Roza E, et al. Neurotransmitters key factors in neurological and neurodegenerative disorders of the central nervous system. International Journal of Molecular Sciences 2022;23(11):5954.
• 11. Akyuz E, Arulsamy A, Aslan FS, et al. An expanded narrative review of neurotransmitters on alzheimer’s disease: The role of therapeutic interventions on neurotransmission. Mol Neurobiol 2025;62,1631–1674.
• 12. Velikic G, Maric DM, Maric DL, et al. Harnessing the stem cell niche in regenerative medicine: Innovative avenue to combat neurodegenerative diseases. International Journal of Molecular Sciences 2024;25(2):993.
• 13. Colucci-D’Amato L, Speranza L, Volpicelli F. Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. International Journal of Molecular Sciences 2020;21(20):7777.
• 14. Rust R, Nih LR, Liberale L, et al. Brain repair mechanisms after cell therapy for stroke. Brain 2024;147(10),3286-3305.
• 15. Numakawa T, Odaka H. The role of neurotrophin signaling in age-related cognitive decline and cognitive diseases. International Journal of Molecular Sciences 2022;23(14):7726.
• 16. Chen Y, Qin C, Huang J, et al. The role of astrocytes in oxidative stress of central nervous system: A mixed blessing. Cell Prolif 2020;53:e12781.
• 17. Girotra P, Behl T, Sehgal A, et al. Investigation of the molecular role of brain-derived neurotrophic factor in Alzheimer’s Disease. J Mol Neurosci 2022;72,173–186.
• 18. Severini C. Neurotrophic factors in health and disease. Cells 2022;12(1),47.
• 19. Stansberry WM and Pierchala BA. Neurotrophic factors in the physiology of motor neurons and their role in the pathobiology and therapeutic approach to amyotrophic lateral sclerosis. Front. Mol. Neurosci 2023;16:1238453.
• 20. Cheng Y, Song H, Ming GL, et al. Epigenetic and epitranscriptomic regulation of axon regeneration. Mol Psychiatry 2023;28,1440–1450.
• 21. Andoh M, Koyama R. Microglia regulate synaptic development and plasticity. Develop Neurobiol 2021;81:568–590.
• 22. Zhou Y, Shao A, Yao Y, et al. Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury. Cell Commun Signal 2020;18,62.
• 23. Wang C, Zong S, Cui X, et al. The effects of microglia-associated neuroinflammation on Alzheimer’s disease. Front. Immunol 2023;14:1117172.
• 24. Fornari Laurindo L, Aparecido Dias J, Cressoni Araújo A, et al. Immunological dimensions of neuroinflammation and microglial activation: Exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression. Front. Immunol 2024;14:1305933.
• 25. Seo DY, Heo JW, Ko JR, et al. Exercise and neuroinflammation in health and disease. Int Neurourol J 2019;23:S82-S92.
• 26. Azam S, Haque ME, Balakrishnan R, et al. The Ageing Brain: Molecular and cellular basis of neurodegeneration. Front. Cell Dev. Biol 2021;9:683459.
• 27. Augusto-Oliveira M, Arrifano GP, Delage CI, et al. Plasticity of microglia. Biol Rev 2022;97:217-250.
• 28. Shah M, Suresh S, Paddick J, et al. Age-related changes in responsiveness to non-invasive brain stimulation neuroplasticity paradigms: A systematic review with meta-analysis. Clinical Neurophysiology 2024;162:53-67.
• 29. Błaszczyk JW. Energy Metabolism decline in the aging brain—pathogenesis of neurodegenerative disorders. Metabolites 2020;10(11):450.
• 30. Ding Y, Liu C, Zhang Y. Aging-related histone modification changes in brain function. Ibrain 2023;9:205-213.
• 31. Ham S, Lee SJV. Advances in transcriptome analysis of human brain aging. Exp Mol Med 2020;52,1787-1797.
• 32. Martin-Aragon S, and Bermejo-Bescós P. Homeostatic plasticity and therapeutic approaches in. Biogenic Amines in Neurotransmission and Human Disease 2019;23.
• 33. Berson A, Nativio R, Berger SL, et al. Epigenetic regulation in neurodegenerative diseases. Trends in Neurosciences 2018;41(9),587-598.
• 34. Mercerón-Martínez D, Ibaceta-González C, Salazar C, et al. Alzheimer’s disease, neural plasticity, and functional recovery. Journal of Alzheimer's Disease 2021;82(s1),S37-S50.
• 35. Das N, Raymick J. Sarkar S. Role of metals in Alzheimer’s disease. Metab Brain Dis 2021;36,1627–1639.
• 36. Colavitta MF and Barrantes FJ. Therapeutic strategies aimed at improving neuroplasticity in Alzheimer Disease. Pharmaceutics 2023;15(8):2052.
• 37. Lissek T. Aging, adaptation and maladaptation. Front. Aging 2023;4:1256844.
• 38. Cordeiro A, Gomes C, Bicker J, et al. Aging and cognitive resilience: Molecular mechanisms as new potential therapeutic targets. Drug Discovery Today 2024;104093.
• 39. Giguère N, Burke Nanni S, Trudeau LE. On Cell Loss and selective vulnerability of neuronal populations in Parkinson's Disease. Front Neurol 2018;9:455.
• 40. Appelbaum LG, Shenasa MA, Stolz L, et al. Synaptic plasticity and mental health: Methods, challenges and opportunities. Neuropsychopharmacol 2023;48,113–120.
• 41. Lanza K, Bishop C. Dopamine D3 receptor plasticity in Parkinson’s Disease and L-DOPA-induced dyskinesia. Biomedicines 2021;9(3):314.
• 42. Kim HJ, Mason S, Foltynie T, et al. Motor complications in Parkinson's Disease: 13-Year follow-up of the CamPaIGN cohort. Mov Disord 2020;35:185-190.
• 43. Klæstrup IH, Just MK, Holm KL et al. Impact of aging on animal models of Parkinson's disease. Front. Aging Neurosci 2022;14:909273.
• 44. Rehman A, Saba T, Mujahid M et al. Parkinson’s Disease detection using hybrid LSTM-GRU deep learning model. Electronics 2023;12(13):2856.
• 45. Tan B, Shishegar R, Poudel GR et al. Cortical morphometry and neural dysfunction in Huntington’s disease: A review. Eur J Neurol 2021;28:1406-1419.
• 46. Joy MT and Carmichael ST. Encouraging an excitable brain state: Mechanisms of brain repair in stroke. Nat Rev Neurosci 2021;22,38-53.
• 47. Cepeda C and Levine MS. Synaptic Dysfunction in Huntington’s Disease: Lessons from genetic animal models. The Neuroscientist 2022;28(1):20-40.
• 48. Speidell A, Bin Abid N, Yano H. Brain-derived neurotrophic factor dysregulation as an essential pathological feature in huntington’s disease: Mechanisms and potential therapeutics. Biomedicines 2023;11(8):2275.
• 49. Dejanovic B, Sheng M, Hanson JE. Targeting synapse function and loss for treatment of neurodegenerative diseases. Nat Rev Drug Discov 2024;23,23-42.
• 50. Yang Z, Zou Y, Wang L. Neurotransmitters in prevention and treatment of Alzheimer’s Disease. International Journal of Molecular Sciences 2023;24(4):3841.
• 51. Kumar J, Patel T, Sugandh F, et al. Innovative approaches and therapies to enhance neuroplasticity and promote recovery in patients with neurological disorders: A narrative review. Cureus 2023;15(7),e41914.
• 52. Begenisic T, Pavese C, Aiachini B, et al. Dynamics of biomarkers across the stages of traumatic spinal cord injury-implications for neural plasticity and repair. Restorative Neurology and Neuroscience 2021;39(5),339-366.
• 53. Aderinto N, Olatunji G, Muili A, et al. A narrative review of non-invasive brain stimulation techniques in neuropsychiatric disorders: Current applications and future directions. The Egyptian Journal of Neurology, Psychiatry and Neurosurgery 2024;60(1),50.
• 54. Jangwan NS, Ashraf GM, Ram V, et al. Brain augmentation and neuroscience technologies: Current applications, challenges, ethics and future prospects. Front. Syst. Neurosci 2022;16:1000495.
• 55. Policastro G, Brunelli M, Tinazzi M, et al. Cytokine‐, Neurotrophin‐, and Motor Rehabilitation‐induced plasticity in Parkinson’s Disease. Neural Plasticity 2020;1,8814028.
• 56. Arida RM and Teixeira-Machado L. The contribution of physical exercise to brain resilience. Front. Behav. Neurosci 2021;14:626769.
• 57. Franco GA, Interdonato L, Cordaro M, et al. Bioactive compounds of the mediterranean diet as nutritional support to fight neurodegenerative disease. International Journal of Molecular Sciences 2023;24(8):7318.
• 58. Ballesteros S, Voelcker-Rehage C, Bherer L. Editorial: Cognitive and brain plasticity induced by physical exercise, cognitive training, video games, and combined interventions. Front. Hum. Neurosci 2018;12:169.
• 59. Silva NCBS, Barha CK, Erickson KI, et al. Physical exercise, cognition, and brain health in aging. Trends in Neurosciences 2024;47(6),402-417.
• 60. Heidarpanah A. A review of transcranial magnetic stimulation and Alzheimer's disease. arXiv: 2022;2208.13905.
• 61. Cirillo G, Pepe R, Siciliano M, et al. Long-Term Neuromodulatory effects of repetitive transcranial magnetic stimulation (rTMS) on plasmatic matrix metalloproteinases (MMPs) levels and visuospatial abilities in mild cognitive impairment (MCI). International Journal of Molecular Sciences 2023;24(4):3231.
• 62. Idlett-Ali SL, Salazar CA, Bell MS et al. Neuromodulation for treatment-resistant depression: Functional network targets contributing to antidepressive outcomes. Front. Hum. Neurosci 2023;17:1125074.
• 63. Yang C, Guo Z, Peng H, et al. Repetitive transcranial magnetic stimulation therapy for motor recovery in Parkinson's disease: A Meta-analysis. Brain Behav 2018;8:e01132.
• 64. Bagattini C, Zanni M, Barocco F et al. Enhancing cognitive training effects in Alzheimer’s disease: rTMS as an add-on treatment. Brain Stimulation 2020;13(6),1655-1664.
• 65. Zhang W, Xiao D, Mao Q, et al. Role of neuroinflammation in neurodegeneration development. Sig Transduct Target Ther 2023;8,267.
• 66. Liu CY, Wang X, Liu C, et al. Pharmacological targeting of microglial activation: New therapeutic approach. Front. Cell. Neurosci 2019;13:514.
• 67. Bellingacci L, Canonichesi J, Mancini A, et al. Cytokines, synaptic plasticity and network dynamics: a question of balance. Neural Regeneration Research 2023;18(12),2569.
• 68. Rizzo FR, Musella A, De Vito F, et al. Tumor necrosis factor and interleukin‐1β modulate synaptic plasticity during neuroinflammation. Neural plasticity 2018;1,8430123.
• 69. Eva L, Pleș H, Covache-Busuioc RA, et al. A Comprehensive review on neuroimmunology: Insights from multiple sclerosis to future therapeutic developments. Biomedicines 2023;11(9):2489.
• 70. De Gioia R, Biella F, Citterio G, et al. Neural stem cell transplantation for neurodegenerative diseases. International Journal of Molecular Sciences 2020;21(9):3103.
• 71. Huang P, and Zhang M. Magnetic resonance imaging studies of neurodegenerative disease: From methods to translational research. Neurosci 2023;Bull 39,99-112.
• 72. Loftus JR, Puri S, Meyers SP. Multimodality imaging of neurodegenerative disorders with a focus on multiparametric magnetic resonance and molecular imaging. Insights Imaging 2023;14,8.
• 73. Herbet G and Duffau H. Revisiting the functional anatomy of the human brain: toward a meta-networking theory of cerebral functions. Physiological Reviews 2020;100(3),1181-1228.
• 74. Annavarapu RN, Kathi S, Vadla VK. Non-invasive imaging modalities to study neurodegenerative diseases of aging brain. Journal of Chemical Neuroanatomy 2019;95,54-69.
• 75. Pissarek M. Positron emission tomography in the inflamed cerebellum: Addressing novel targets among g protein-coupled receptors and immune receptors. Pharmaceutics 2020;12(10):925.
• 76. Yeh CH, Jones DK, Liang X, et al. Mapping structural connectivity using diffusion MRI: Challenges and opportunities. J Magn Reson Imaging 2021;53:1666-1682.
• 77. Hampel H, Lista S, Neri C, et al. Time for the systems-level integration of aging: resilience enhancing strategies to prevent Alzheimer’s disease. Progress in Neurobiology 2019;181,101662.
• 78. Hollunder B, Rajamani N, Siddiqi SH, et al. Toward personalized medicine in connectomic deep brain stimulation. Progress in Neurobiology 2022;210,102211.
• 79. Hampel H, Nisticò R, Seyfried NT et al. Alzheimer precision medicine initiative. Omics sciences for systems biology in Alzheimer’s disease: State-of-the-art of the evidence. Ageing Research Reviews 2021;69,101346.
• 80. Wilson DM, Cookson MR, Van Den Bosch L, et al. Hallmarks of neurodegenerative diseases. Cell 2023;186(4),693-714.
• 81. Sha Z, Xu J, Li N, et al. Regulatory molecules of synaptic plasticity in anxiety disorder. International Journal of General Medicine 2023;2877-2886.
• 82. Hogan MK, Hamilton GF and Horner PJ. Neural stimulation and molecular mechanisms of plasticity and regeneration: A review. Front Cell Neurosci 2020;14:271.
• 83. Lontay B, Kiss A, Virág L, et al. How do post-translational modifications influence the pathomechanistic landscape of huntington’s disease? A comprehensive review. International Journal of Molecular Sciences 2020;21(12):4282.
• 84. Clark C, Dayon L, Masoodi M, et al. An integrative multi-omics approach reveals new central nervous system pathway alterations in Alzheimer’s Disease. Alz Res Therapy 2021;13,71.
• 85. Aerqin Q, Wang ZT, Wu KM, et al. Omics-based biomarkers discovery for Alzheimer's Disease. Cell. Mol. Life Sci 2022;79,585.
• 86. Wolpaw JR and Thompson AK. Enhancing neurorehabilitation by targeting beneficial plasticity. Front. Rehabil. 2023;4:1198679.
• 87. Gupta A, Vardalakis N, Wagner FB. Neuroprosthetics: From sensorimotor to cognitive disorders. Commun Biol 2023;6,14.
• 88. WangDrigas A, Sideraki A. Brain neuroplasticity leveraging virtual reality and brain–computer interface technologies. Sensors 2024;24(17):5725.
• 89. Belkacem AN, Jamil N, Khalid S, et al. On closed-loop brain stimulation systems for improving the quality of life of patients with neurological disorders. Front. Hum. Neurosci 2023;17:1085173.
• 90. Osman NM, Refai MK, Elshafey K, et al. A literature review of bcis for assisting scis with disabilities from a developmental point ff view and potential future trends. Journal of Al-Azhar University Engineering Sector 2024;53-83.