ROLE OF TOLL-LIKE RECEPTORS IN ALZHEIMER’S DISEASE

E. Mazzon¹, T. Paolucci² and O. Trubiani^3*

¹ Department of Medical, Oral and Biotechnological Sciences, University “G. D’Annunzio” of Chieti-Pescara, Chieti, Italy;
² Department of Medicine and Ageing Sciences, University “G. D’Annunzio” of Chieti‐Pescara, Chieti, Italy;
³ Department of Innovative Technologies in Medicine & Dentistry, University “G. D’Annunzio” of Chieti‐Pescara, Chieti, Italy.

*Correspondence to:
Oriana Trubiani,
Department of Innovative Technologies in Medicine & Dentistry,
University “G. d’Annunzio” Chieti-Pescara,
66100 Chieti, Italy.
e-mail: trubiani@unich.it

Received: 05 February, 2025 Accepted: 10 March, 2025

ISSN 2279-5855 print ISSN 2974-6345 online. Copyright © by BIOLIFE 2025 This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

ABSTRACT

Toll-like receptors (TLRs) are a group of pattern recognition receptors (PRRs) that play a key role in both infections and innate immunity. To date, 11 TLRs have been described that recognize pathogen-associated molecular patterns (PAMPs) expressed on infectious agents. In Alzheimer’s disease (AD), TLRs modulate cytokine-mediated inflammation and participate in the innate immune response by mediating neuroinflammation. TLRs modulate the immune system and participate in the clearance of amyloid-beta (Aβ) in AD. Aβ molecules activate the immune system and TLRs can interact with NOD-like receptors (NLRs) to activate inflammasomes. IL-1 is generated by microglia in response to Aβ plaques  and plays a crucial role in AD when it is overproduced by causing inflammation and fever. TLR activation in AD leads to the production of pro-inflammatory cytokines such as IL-1 that induce neuroinflammation and worsen AD.

KEYWORDS: Alzheimer’s Disease, neurodegeneration, Toll-like receptor, pattern recognition receptor, inflammation

INTRODUCTION

Toll-like receptor (TLR) family proteins are a group of pattern recognition receptors (PRRs), which play a fundamental role in pathogen recognition and activation of innate immunity (1).  In the innate immune response, PRRs play a critical role system by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) (2). There are 11 TLRs, numbered TLR1 through TLR11 (Table I).

Table I. The biological effects of TLRs.

TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize PAMPs that are expressed on infectious agents and mediate the production of cytokines necessary for the development of effective immunity (3). PRRs play a key role in the innate immune system by recognizing PAMPs and damage-associated molecular patterns (DAMPs).  In Alzheimer’s disease (AD), TLRs have a dual role: They modulate cytokine-mediated inflammation, and they intervene in the immune response “in toto”. TLRs participate in neuroinflammation in AD and TLR2, TLR4 and TLR9, are activated by amyloid-beta (Aβ) plaques (4).

DISCUSSION

Aβ functions as a DAMP, triggering TLR-mediated inflammatory pathways (5). TLRs are expressed by microglia cells that inhabit the brain and mediate their activation (6). Aβ plaques are capable of activating microglia, causing a neuroinflammatory cascade with cytokine production.

Microglia cells are similar to macrophages and when they come into contact with Aβ plaques, they phagocytose them, releasing inflammatory compounds that exacerbate AD pathology (7).  The production of cytokines through TLR activation leads to the activation of NF-κB, which leads to the transcription and translation of inflammatory cytokines such as IL-1, TNF, IL-6, and IL-18. At the same time, chemokines are also generated and released which contributes to the neuroinflammation (8).

It is possible that anti-inflammatory cytokines, such as IL-10, IL-37, and IL-38, are also released, but probably in insufficient amounts to inhibit inflammation in AD (9). Therefore, cytokine dysregulation is one of the important features in this neurodegenerative disease. In AD, TLRs not only modulate the immune system, but also participate in Aβ clearance. In fact, TLR4 promotes microglia phagocytosis to promote Aβ clearance (10). The effect of TLR4 also improves astrocyte degradation (11). Regulating TLR could improve the immune system with positive effects on both Aβ clearance and local and systemic inflammation. Activation of TLR9 has neuroprotective effects and can also have a positive effect on inflammation, as has been demonstrated in experimental models (12).

TLRs are dysregulated in AD and do not permit the correct immune response. Aβ molecules continuously activate the immune system to overreact. TLRs can interact with NOD-like receptors (NLRs) to activate inflammasomes, such as NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), exacerbating inflammation through caspase-1 activation and the release of cytokines such as IL-1β. It is known that some TLRs, such as TLR2, TLR4, and TLR9, specifically participate in the pathological effect that occurs in AD (13) (Fig.1).

Fig. 1. Toll-like receptors (TLRs)-2 and 4 start a cascade that leads to inflammation and immunoregulation in Alzheimer’s disease (AD) (arrows mean activation).

TLR2 recognizes Aβ oligomers, contributes to the production of pro-inflammatory cytokines, and is linked to cognitive decline in AD, while TLR4 promotes Aβ clearance. TLR9 has been shown to be neuroprotective and interacts with mitochondrial DNA released from damaged neurons (14). These effects suggest a role for TLR9 in AD therapy. Recently, it has been seen that rat TLR1 (or CD281) polyclonal antibody (concentration: 0.25 mg/ml purified IgG) work with the selective affinity and could be used to treat AD (15). Targeting and modulating TLR could be an important new therapeutic strategy, as currently AD drugs are limited and nonspecific (16). One of the interesting strategies would be to stimulate the neuroprotective TLR9 with the hope of increasing the clearance of Aβ (17).  The specific inhibition of TLR2 and 4 would reduce the production of pro-inflammatory cytokines improving the health status in AD (18). In addition, the therapeutic use of inhibitory cytokines such as IL-37 and IL-38 that significantly reduce IL-1b could be another therapeutic option (19).

IL-1 and Alzheimer’s disease (AD)

IL-1 is an important cytokine of the immune system that plays a crucial role in AD (20). In addition to being an immune molecule, when it is overproduced, IL-1 causes inflammation and fever (21). It is produced in the brain mostly by microglia in response to Aβ plaques.  This cytokine can aggregate Aβ plaques and cause hyperphosphorylation of tau protein, worsening neuronal dysfunction and synaptic efficiency (22).

Targeting IL-1 can improve neuroinflammation in AD. IL-1 and TLR have similar pathways and interact to increase the inflammatory response (23,24). In fact, TLR activation in microglia leads to increased signaling of MyD88, the precursor of IL-1, which in turn re-stimulates IL-1. This creates a vicious cycle where IL-1 induces IL-1 to create the chronic and self-sustaining inflammatory state observed in AD (25). NLRP3 is a multiprotein complex that is part of the innate immune system and acts as an intracellular sensor that detects a broad range of microorganisms (26). When activated, it leads to the cleavage of pro-caspase-1 into its active form, caspase-1, triggering an inflammatory response with the release of the pro-inflammatory cytokine IL-1 (27,28).

Activation of NLRP3 in microglia plays a significant neuroinflammatory role in the pathogenesis of AD and potential therapies have now been shown to target the NLRP3 inflammasome (26). Microglial cells recognize Aβ and activate the NLRP3 inflammasome, an effect which is also exerted by hyperphosphorylated tau aggregates. In AD, excessive production of IL-1β contributes to neuronal damage, and chronic activation of NLRP3 impairs phagocytosis of microglial cells (29).

CONCLUSIONS

In conclusion, TLR activation in AD leads to the production of pro-inflammatory cytokines and results in neuroinflammation. Targeting TLRs with different specific strategies or inhibiting pro-inflammatory cytokines could be used for new therapies that are currently needed due to the lack of pharmacological tools. AD is increasing in the population, especially in the elderly, and continued research is vital for creating new therapies. In AD, TLRs play an important role in cytokine-mediated neuroinflammation and also in the clearance of Aβ. Targeting TLRs represents a promising therapeutic option in this severe debilitating disease.

Conflict of interest

The authors declare that they have no conflict of interest.

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