Neuronal plasticity and its role in Alzheimer's disease and Parkinson's disease

Abstract

Neuronal plasticity, the brain's ability to adapt structurally and functionally, is essential for learning, memory, and recovery from injuries. In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, this plasticity is disrupted, leading to cognitive and motor deficits. This review explores the mechanisms of neuronal plasticity and its effect on Alzheimer's disease and Parkinson's disease. Alzheimer's disease features amyloid-beta plaques and tau tangles that impair synaptic function, while Parkinson's disease involves the loss of dopaminergic neurons affecting motor control. Enhancing neuronal plasticity offers therapeutic potential for these diseases. A systematic literature review was conducted using databases such as PubMed, Scopus, and Google Scholar, focusing on studies of neuronal plasticity in Alzheimer's disease and Parkinson's disease. Data synthesis identified key themes such as synaptic mechanisms, neurogenesis, and therapeutic strategies, linking molecular insights to clinical applications. Results highlight that targeting synaptic plasticity mechanisms, such as long-term potentiation and long-term depression, shows promise. Neurotrophic factors, advanced imaging techniques, and molecular tools (e.g., clustered regularly interspaced short palindromic repeats and optogenetics) are crucial in understanding and enhancing plasticity. Current therapies, including dopamine replacement, deep brain stimulation, and lifestyle interventions, demonstrate the potential to alleviate symptoms and improve outcomes. In conclusion, enhancing neuronal plasticity through targeted therapies holds significant promise for treating neurodegenerative diseases. Future research should integrate multidisciplinary approaches to fully harness the therapeutic potential of neuronal plasticity in Alzheimer's disease and Parkinson's disease.

Keywords: Alzheimer’s disease; Parkinson’s disease; long-term depression; long-term potentiation; neuroinflammation; neuronal plasticity; synaptic plasticity.

Figure 1

Mechanisms of LTD, presynaptic LTP, and postsynaptic LTP. (A) LTD is triggered by simultaneous stimulation of parallel and CFs and necessitates an increase in postsynaptic Ca²⁺ levels. (B) Presynaptic LTP can be induced by brief parallel fiber stimulations at 4–8 Hz, regulated by a retrograde signaling mechanism involving cannabinoids. eCBs are released from the postsynaptic membrane following high-frequency bursts of parallel fiber activity, which depend on the activation of postsynaptic mGlu1 receptors. These eCBs then act retrogradely on presynaptic CB1R, leading to a decrease in transmitter release. (C) Postsynaptic LTP can be induced by stimulating parallel fibers at 1 Hz and requires low levels of Ca²⁺ in Purkinje cells. Reproduced with the permission from Hoxha et al. (2016). Published by Frontiers under license CC BY 4.0. CB1R: Cannabinoid 1 receptors; CF: climbing fibers; eCBs: endogenous cannabinoids; LTD: long-term depression; LTP: long-term potentiation.

Figure 2

Representative illustration of key scaffold proteins and their respective domains. The molecular components critical to synaptogenesis, focusing on scaffold proteins that structure synaptic networks essential for neural communication. Highlighted proteins include Liprin-α, ELKS/CAST (ERC1, LIPRIN-α, and SYD-2/CAZ-associated structural protein), Piccolo, Bassoon, and PSD95. These scaffold proteins organize pre-synaptic vesicle docking within the cytomatrix and contribute to the formation of PSDs, electron-dense regions essential for synaptic stability and function. The diagram, though not scaled, provides a detailed view of interactions among these proteins, emphasizing their roles in supporting the architecture and connectivity of synapses, fundamental for information processing and storage in the nervous system. Reproduced with the permission from Qi et al. (2022). Published by Frontiers under license CC BY 4.0. PSD: postsynaptic density.

Figure 3

Illustration of the protein network within excitatory synapses, emphasizing the interactions among different synaptic proteins and CAMs. The figure shows the intricate network of synaptic proteins essential for establishing and maintaining excitatory synapses. Genetic screenings and homologous cloning approaches have identified key players like Liprin-α, which interacts with LAR transmembrane proteins to recruit ELKS/CAST at the active zone, promoting synaptic vesicle docking and efficient neurotransmission. CAMs, including Syncam1, Neurexin, Neuroligin, and NGL-3, serve as critical bridges between pre- and post-synaptic components, aligning and stabilizing synaptic structures through interactions with scaffold proteins. The LAR-RPTPs and their ligands, such as NGL-3 and SALMs, further support synapse formation and stability. Structural integrity is provided by the cytoskeleton, with actin filaments dynamically regulated by proteins like profilin and cofilin, ensuring the formation and maintenance of dendritic spines and axonal growth cones. Actin remodeling, driven by neural activity, significantly impacts synaptic plasticity and structure. Activity-dependent mechanisms involving calcium signaling, protein kinases, transcription factors, and local translation facilitate synaptogenesis by stabilizing synaptic connections. Additionally, neural activity governs the release of neurotrophic factors, particularly BDNF, which modulates synaptic growth and plasticity via Trk receptors and local protein synthesis at synaptic sites. The figure has been reproduced with the permission from Qi et al. (2022). Published by Frontiers under license CC BY 4.0. CAMs: Cell adhesion molecules; LAR-RPTPs: leukocyte common antigen-related protein-tyrosine phosphatases; NGL-3: netrin-G ligand-3; SALMs: synaptic adhesion-like molecules.

Figure 4

Timeline of historical milestones in the study of neuronal plasticity, AD, and PD. The figure illustrates key advancements from the foundational studies on neuroplasticity mechanisms in the 1970s through the discovery of pathological markers in AD, to recent developments in gene therapy aimed at preserving neuronal plasticity in neurodegenerative diseases. This visual progression highlights the evolution of research and therapeutic approaches over five decades, emphasizing the contributions of neuroimaging, genetic engineering, and precision medicine in understanding and combating AD and PD. AD: Alzheimer’s disease; Aβ: amyloid-beta; LTD: long-term depression; LTP: long-term potentiation; PD: Parkinson’s disease.