Journal of Clinical & Experimental Neuroimmunology
Open Access

Alzheimer's disease; Neuroinflammation; Immunotherapy; Microglia; Amyloid-β; Tau; Innate immunity; Adaptive immunity; Neurodegeneration

Introduction

Alzheimer's disease (AD) represents a significant global health challenge, affecting millions worldwide and imposing a substantial burden on healthcare systems. This progressive neurodegenerative condition is characterized by a gradual decline in cognitive function, memory loss, and behavioral changes. The classical pathological hallmarks of AD are the accumulation of extracellular Aβ plaques and intracellular NFTs composed of hyperphosphorylated tau protein. However, over the past two decades, the role of chronic neuroinflammation, orchestrated by both innate and adaptive immune responses within the central nervous system (CNS), has emerged as a critical contributor to AD pathogenesis and progression. Microglia, the resident immune cells of the brain, play a dual role in AD [1-3]. Under physiological conditions, they are involved in clearing Aβ and cellular debris, maintaining tissue homeostasis. However, in AD, chronic activation of microglia can lead to the sustained release of pro-inflammatory cytokines, chemokines, and reactive oxygen species, exacerbating neuronal damage and contributing to the neurodegenerative cascade. Furthermore, peripheral immune cells can infiltrate the brain parenchyma and contribute to the inflammatory milieu. This review delves into recent advances in targeting immune pathways for AD, providing insights into the potential of immunotherapeutic approaches for disease modification and highlighting the complexities and challenges involved.

Results

Recent research has identified several key immune pathways as promising therapeutic targets for AD. One prominent area of investigation focuses on modulating microglial activity. Studies have demonstrated that shifting microglia from a pro-inflammatory (M1) phenotype, characterized by the release of TNF-α and IL-1β, to an anti-inflammatory (M2) phenotype, associated with the production of anti-inflammatory cytokines like IL-10 and TGF-β, can promote Aβ clearance, enhance neurotrophic support, and provide neuroprotection . Several approaches are being explored to achieve this polarization shift, including targeting specific receptors such as TREM2 and CD33, and modulating intracellular signaling pathways like NF-κB. The innate immune response, particularly the complement system, has also garnered considerable attention in AD research. The complement cascade, a crucial component of innate immunity, has been implicated in Aβ deposition, synaptic dysfunction, and neuroinflammation . Studies have shown that inhibiting specific complement components, such as C1q and C3, can attenuate neuroinflammation and reduce neuronal damage in preclinical models. Therefore, targeting the complement system is being explored as a potential therapeutic strategy. The adaptive immune response, involving T and B lymphocytes, plays a more complex role in AD. While some studies suggest that certain T cell subsets, such as regulatory T cells (Tregs), can promote Aβ clearance and exert neuroprotective effects, other studies indicate that pro-inflammatory T cells, such as Th1 and Th17 cells, can exacerbate neuroinflammation and contribute to neuronal damage . Therefore, modulating T cell responses, for example by promoting Treg activity or inhibiting pro-inflammatory T cell infiltration, is being investigated as a potential therapeutic avenue. Immunotherapeutic strategies, including both active and passive immunization against Aβ, have been extensively studied in preclinical and clinical settings . Active immunization aims to stimulate the patient's own immune system to produce antibodies against Aβ, while passive immunization involves administering pre-formed anti-Aβ antibodies [4]. Although initial clinical trials of active immunization were hampered by adverse events, such as meningoencephalitis due to T cell-mediated autoimmune responses , advancements in vaccine design and delivery methods have led to the development of safer and more targeted approaches. Recent advances in antibody engineering have also facilitated the development of more effective anti-Aβ antibodies for passive immunization. These next-generation antibodies can target specific Aβ species, such as soluble oligomers, which are considered to be particularly toxic to synapses, and have demonstrated promising results in preclinical studies and some recent clinical trials . Beyond targeting Aβ, research has also explored targeting other immune mediators implicated in AD, such as pro-inflammatory cytokines like TNF-α and IL-1β [5-8]. Clinical trials investigating the efficacy of anti-TNF-α therapy in AD have yielded mixed results, highlighting the complexity of targeting cytokine pathways and the need for more targeted approaches. The role of peripheral inflammation in AD is also gaining increasing recognition. Systemic infections, chronic inflammatory conditions, and even lifestyle factors like diet and exercise can influence peripheral inflammation and subsequently impact neuroinflammation and cognitive decline in AD. Therefore, targeting peripheral inflammation through anti-inflammatory drugs, lifestyle interventions, and management of comorbid conditions may represent a beneficial therapeutic strategy. Finally, genetic studies have identified several immune-related genes as significant risk factors for AD, providing further evidence for the crucial role of the immune system in disease pathogenesis. For instance, variants in TREM2, a gene encoding a microglial receptor involved in phagocytosis and inflammation regulation, have been strongly associated with increased AD risk . These genetic findings underscore the importance of understanding the intricate interplay between genetic predisposition and immune responses in AD development.

Discussion

The findings presented in this review underscore the growing recognition of the immune system's pivotal role in AD pathogenesis and the potential of immunotherapeutic strategies for disease modification. Modulating microglial activity, targeting the complement system, and carefully modulating T cell responses are among the promising therapeutic avenues being actively pursued. Immunotherapies targeting Aβ have shown some degree of promise, although further research is crucial to optimize these approaches, minimize potential adverse events, and identify appropriate patient populations for these interventions. Targeting other immune mediators, such as specific cytokines, and addressing peripheral inflammation may also offer therapeutic benefits. The identification of immune-related risk genes for AD further emphasizes the importance of the immune system in disease development and highlights the potential for personalized immunotherapeutic approaches based on individual genetic and immunological profiles. However, the complex interplay between different immune components and their dynamic roles at different stages of AD necessitates further investigation. Future research should prioritize identifying specific therapeutic targets, developing more selective and targeted immunomodulatory agents, and conducting well-designed clinical trials to translate preclinical findings into effective clinical therapies that can meaningfully impact the course of this devastating disease.

Conclusion

The immune system plays a multifaceted and critical role in the pathogenesis of Alzheimer's disease. Recent advances in understanding the complex interactions between the immune system and neurodegeneration have opened new and exciting avenues for therapeutic intervention. Targeting immune pathways, through a variety of immunotherapeutic strategies, holds significant promise for modifying disease progression, delaying cognitive decline, and ultimately improving outcomes for individuals living with AD. Continued research efforts are essential to refine these approaches, overcome existing challenges, and translate promising preclinical findings into effective and safe clinical therapies that can make a tangible difference in the lives of those affected by this debilitating disease.

1. Abdelaziz M, Samer Kamel S, Karam O, Abdelrahman (2011)Evaluation of E-learning program versus traditional lecture instruction for undergraduate nursing students in a faculty of nursing. Teaching and Learning in Nursing 6: 50 – 58.

Google Scholar, Crossref

2. Vaona A, Banzi R, Kwag KH, Rigon G, Cereda D, Pecoraro V, Moja L (2018)E-learning for health professionals. Cochrane Database Syst Rev 1: Cd011736.

Indexed at, Google Scholar, Crossref

3. Hodges BD, Kuper A (2012)Theory and practice in the design and conduct of graduate medical education. Academic Medicine 87(1), 25–33.

Indexed at, Google Scholar, Crossref

4. Mayes T, De Freitas S (2013)Review of e-learning theories, frameworks, and models.
5. Hadadgar A, Changiz T, Masiello I, Dehghani Z, Mirshahzadeh N, et al. (2016)Applicability of the theory of planned behavior in explaining the general practitioners eLearning use in continuing medical education. BMC Med Educ 16: 215.

Google Scholar, Crossref

6. Babbie E, Benaquisto L (2014)Fundamentals of Social Research Methods (3rd Cdn.). Toronto: Nelson Education Ltd.
7. Ajzen I (1991) The theory of planned behavior. Orgnizational Behavior and Human Decision Processes, 50: 179–211.

Google Scholar, Crossref

8. Alhojailan MI (2012)Thematic analysis: a critical review of its process and evaluation. West East Journal of Social Sciences 1: 39 – 47.

Google Scholar