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Therapeutic implications of necroptosis activation in Alzheimer´s disease

Alzheimer's Research & Therapy volume 16, Article number: 275 (2024) Cite this article

Abstract

In recent years, a growing body of research has unveiled the involvement of the necroptosis pathway in the pathogenesis of Alzheimer’s disease (AD). This evidence has shed light on the mechanisms underlying neuronal death in AD, positioning necroptosis at the forefront as a potential target for therapeutic intervention. This review provides an update on the current knowledge on this emerging, yet rapidly advancing topic, encompassing all published studies that present supporting proof of the role of the necroptosis pathway in the neurodegenerative processes of AD. The implication of misfolded tau and amyloid-β (Aβ) aggregates is highlighted, with evidence suggesting their direct or indirect involvement in necroptosis activation. In summary, the review underscores the significance of understanding the complex interplay between necroptosis, protein aggregates, and neurodegeneration in AD. The findings advocate for a comprehensive approach, combining therapeutic and early diagnostic strategies, to intervene in the disease process before irreversible damage occurs.

Background

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the leading cause of dementia [1]. Early onset (< 65 years) familial AD is caused by genetic mutations; however, this form of the disease is rare, accounting for less than 5% of cases [2,3,4,5]. The most common form is sporadic late-onset (> 65 years) AD, the cause of which remains unknown, although it has been linked to several risk factors. The greatest risk factors for sporadic AD include older age, genetics (several genes have been identified as increasing the risk of AD, with the ε4 allele of the apolipoprotein E gene having the most significant impact), and having a family history of AD [6,7,8,9]. Moreover, several modifiable risk factors have been linked to the disease, including obesity, physical inactivity, and low education, among others [10].

AD is characterized by progressive cognitive deterioration involving severe memory decline. Brain accumulation of senile plaques composed of aggregated amyloid-β (Aβ), and neurofibrillary tangles constituted of hyperphosphorylated tau, represents the neuropathological hallmark of the disease [11,12,13]. Prominent histopathological features of AD brains include neuroinflammation, synaptic loss, neurodegeneration, and neuronal death [11, 14,15,16,17,18], with the earliest alterations observed in the entorhinal cortex and hippocampus, followed by spread to various cortical areas [11, 19, 20]. Progressive ventricular enlargement with generalized cerebral atrophy can be observed in the AD brain as the result of massive neuronal loss [21]. Although the pathways underlying neuronal dysfunction and loss in AD remain elusive, emerging evidence has implicated the activation of several forms of programmed cell death in this process, including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis [22,23,24,25,26]. Comprehensive studies are needed to determine how these cell death mechanisms interact to contribute to neuronal loss in AD and to identify whether distinct types of cell death are associated with different stages of disease progression. In this context, we specifically examine the role of the necroptosis pathway in neuronal loss in AD.

Necroptosis is a form of programmed cell death that occurs in response to cellular stressors, such as infection or tissue damage [27,28,29]. It is initiated by the activation of receptors such as tumor necrosis factor receptor 1 (TNFR1) or toll-like receptors (TLRs), leading to the formation of a signaling complex called the necrosome [30]. The necrosome consists of receptor-interacting protein kinase 1 (RIPK1) and RIPK3, which recruit and phosphorylate mixed lineage kinase domain-like protein (MLKL) [31]. Phosphorylated MLKL translocates to the plasma membrane, where it oligomerizes and disrupts membrane integrity, triggering inflammation and immune responses [32, 33]. In the last decade, there has been mounting evidence implicating the necroptosis pathway in the pathogenesis of various neurodegenerative diseases [34,35,36,37]. This review outlines the accumulating evidence suggesting necroptosis as a promising therapeutic avenue for AD.

Necroptosis as a potential therapeutic target for AD

The first proof of a role for necroptosis in AD came from a study that found an increase in the components of the necroptosis machinery in AD postmortem brain samples [37]. In addition, using the 5XFAD model of AD, reduced neuronal loss in mice treated with a necroptosis inhibitor was demonstrated [37]. The observation of necroptosis markers in AD brains was later confirmed by other research groups [38,39,40,41,42]. Notably, increasing studies have evidenced the functional implications of targeting necroptosis in experimental AD models, where blocking different components of the pathway (i.e. RIPK1, RIPK3, MLKL), by pharmacological or genetic means, has led to improvements in cognitive performance [41, 43,44,45]. Recent efforts to uncover the initiating factors triggering necroptosis in AD have suggested the involvement of TNF signaling. In this line, the upregulation of key molecules within the TNF pathway, including TNFR1, TNFR2, TNF and FADD, was observed in AD brains, and interestingly, the increased TNFR1 expression occurred specifically in pMLKL and pRIPK3-bearing neurons [38]. Accordingly, intracerebral administration of TNF-α induced necroptosis activation and neuronal loss in the hippocampus of wild-type mice and exacerbated these findings in the APP/PS1 model of AD [40].

While most studies on necroptosis activation in AD have predominantly identified its induction in neurons [37, 41, 42], emerging evidence suggests a broader involvement of the pathway in other cell types. In this context, a study demonstrated increased MLKL levels mostly in microglia following intrahippocampal injection of Aβ oligomers in APP23 mice [46]. Another work provided evidence for the expression of RIPK1, RIPK3 and MLKL in cultured human monocytes treated with Aβ aggregates [47]. In a recent study, necroptosis activation in cerebral endothelial cells of two transgenic AD models (APP/PS1 and APP-KINL−G−F) as well as in human AD brains was demonstrated, which was linked to reduced expression of mNat1/Nat2, a regulator of insulin sensitivity. Recovering cerebral mNAT1 inhibited endothelial necroptosis and improved cognitive function in APP-PS1 mice. In APP-KINL−G−F mice, pharmacological inhibition of RIPK1 reduced endothelial cell loss and cerebrovascular pathology [48]. Together, these studies shed light on contributions from non-neuronal cells to the pathogenic processes associated with AD. Thus, it is imperative to extend our scrutiny beyond neurons and explore the comprehensive landscape of necroptosis involvement across various cell populations, to unveil the potential multifaceted roles of this regulated necrotic pathway in the pathophysiology of AD.

Multiple cellular and molecular processes are altered in AD. Inflammation has been identified as a key factor driving neural injury and the progression of neurodegeneration. Glial cells play a crucial role in maintaining neuronal homeostasis, and their necroptosis-mediated dysfunction may exacerbate neuroinflammatory responses, leading to neuronal injury [49, 50]. Specifically, necroptosis in microglia may promote the release of pro-inflammatory cytokines, which could enhance synaptic loss and neuronal death through the activation of neurotoxic pathways. As mentioned above, necroptosis has been shown to contribute to cerebrovascular damage [48], which is also a significant contributor to neurodegeneration [51]. To fully comprehend the therapeutic potential of inhibiting necroptosis in AD, it is essential to conduct studies that integrate the various aspects of necroptotic signaling in both neuronal and non-neuronal cells. This will allow for a more comprehensive evaluation of how necroptosis contributes to neurodegeneration. In this context, inhibiting the necroptosis pathway could represent a multi-cellular therapeutic strategy, offering neuroprotection either directly by modulating necroptosis-mediated neuronal death or indirectly by targeting non-neuronal cells affected by necroptosis that contribute to neurodegenerative processes.

Most of the studies focusing on the role of necroptosis in AD have consistently demonstrated either direct or indirect involvement of protein aggregates in necroptosis activation. Histological analyses of AD brains have shown high colocalization between tau tangles and necroptotic markers [37, 42]. Moreover, the expression of hyperphosphorylated tau promoted the formation of the necrosome in cell cultures [52]. Additionally, necroptosis activation was demonstrated in the brains of TauP301S mice, which express mutant human tau and develop widespread neurofibrillary tangle-like inclusions [52]. In both in vitro and in vivo models, necroptosis triggered the production of pro-inflammatory cytokines and chemokines including IL-6, IL-15, IFN-1, TNF-α, Ccl2, Ccl5, Cxcl9, and Cxcl10. Necroptosis inhibition reduced the overexpression of these neuroinflammation mediators, as well as pTau-induced neuronal death and microglia hyperactivation, which was assessed by western blotting, qPCR and flow cytometry [52]. Likewise, the burden of Aβ oligomers correlates with necroptosis markers in AD brain samples [41]. Moreover, the injection of Aβ oligomers activated necroptosis, leading to neurodegeneration and memory alterations in wild-type mice [41] and worsened these alterations in APP23 mice [46]. Additional evidence came from studies using transgenic animals based on brain Aβ accumulation. In this context, neuronal necroptosis has been demonstrated in the 5XFAD and APP21 mouse lines, which develop extensive Aβ pathology [37, 46]. In addition, Aβ-induced necroptosis has also been demonstrated in cultured neurons [53,54,55]. A step forward toward unveiling the mechanisms involved was recently achieved as it was demonstrated that Aβ deposition drives tau tangle formation and necroptosis-mediated neuronal death in human neurons xenografted in an APP knock-in mouse model of AD. Notably, blocking the maternally expressed gene 3 (MEG3) reduced the expression of necroptosis markers in the xenografted neurons. This data supports the view of Aβ deposition as the initial trigger of neuropathology in AD and provides proof that necroptosis is induced by MEG3 up-regulation, which occurs downstream of tau accumulation [56]. Collectively, these findings represent compelling evidence demonstrating that both Aβ and tau aggregates serve as catalysts for the initiation of the necroptotic pathway in AD (Fig. 1).

Although current preclinical data is compelling regarding the role of necroptosis as the primary mechanism by which neurons die in the context of AD, the translation of this evidence to the clinic is still in its initial phase. DNL747, developed by Denali Therapeutics, was the first RIPK1 inhibitor tested in a clinical trial for AD. This small molecule was well-tolerated in healthy volunteers and was then tested in two phase I trials involving 16 AD patients. While the drug was safe and well tolerated in both trials, the study indicated that a higher dose would be needed to achieve therapeutic efficacy, which could implicate a potential safety risk [57]. For this reason, it was announced that the studies will be shifted to test the successor molecule DNL788, another inhibitor of RIPK1 with a superior preclinical therapeutic window compared to DNL747. A recent report on the findings of a phase I trial performed on healthy participants revealed that the drug was generally safe and well-tolerated following single and repeated oral doses, supporting further development [58]. Similar results were obtained in a clinical study of SIR-2446, an additional RIPK1 inhibitor developed by Sironax Therapeutics for treating AD and multiple sclerosis, providing support for its continued clinical advancement [59].

Fig. 1
figure 1

Necroptosis activation in AD. Protein misfolding and accumulation leads to activation of the TNF signaling pathway. TNFR1 activation results in the recruitment of RIPK1. In the absence of caspase-8 activity, RIPK1 interacts with RIPK3 to form the necrosome. MLKL is recruited to the complex and phosphorylated by pRIPK3, which triggers its oligomerization and translocation to the plasma membrane, where executes necroptosis

Full size image

While most necroptosis inhibitors currently in clinical trials for various diseases target RIPK1, several compounds targeting the downstream kinase RIPK3, including ponatinib, dabrafenib, and sorafenib, have been approved for cancer treatment [60,61,62]. Although these drugs are not specific RIPK3 inhibitors, preclinical data point to the importance of assessing their efficacy in AD patients [56, 60]. Similarly, although MLKL is the final effector in necroptosis and therefore an important target, there are currently no clinical trials investigating this in the context of AD.

One of the important lessons learned from numerous failed clinical trials for AD is that attempting to revert the extensive damage present in the late stages of the disease, in an effort to recover brain function, is unlikely [61, 62]. An effective treatment before the symptoms arise seems to be a more reasonable approach than attempting to reverse the pathology when the damage is irreversible due to the complexity of the pathological processes triggered [63]. Thus, the simultaneous development of therapeutic and early diagnosis strategies is crucial to efficiently tackle the disease while it is still possible to halt the neurodegeneration process. It remains to be established whether the necroptotic pathway is activated in the preclinical stages of AD and, if so, whether it could serve as an early biomarker or target for the disease. Yet, the evidence indicates a link between necroptosis and protein aggregation, which is largely recognized as an early or even initial event in AD pathogenesis [64]. Moreover, there is evidence that the necroptotic signaling mediates axonal degeneration [34, 65,66,67], and numerous studies suggest that axonal pathology precedes the clinical manifestation of AD [68,69,70,71,72,73]. However, the potential involvement of necroptosis in axonal degeneration has not been demonstrated in the context of AD.

Considering that multiple pathways are affected in AD, the need for combined therapies becomes evident. By targeting different mechanisms, such as protein aggregation and necroptosis, a combined treatment may have a higher chance of success in both improving symptoms and delaying the progression of neurodegeneration. Current evidence strongly supports a role for necroptosis in the pathology of AD, however, further studies are needed to determine the possible implication of the necroptosis pathway in the initial phases of neurodegeneration in the disease.

Conclusions

The evidence presented underscores the significant involvement of necroptosis in AD pathology. Studies have consistently shown the upregulation of necroptosis markers in AD brains and demonstrated the beneficial effects of inhibiting this pathway in experimental models, highlighting its potential as a therapeutic target. Despite promising preclinical findings, clinical translation of necroptosis-targeting therapies is still in the early stages, emphasizing the need for further research to elucidate the role of necroptosis in early neurodegenerative processes.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

AD:

Alzheimer’s disease

MEG3:

maternally expressed gene 3

TNFR1:

tumor necrosis factor receptor 1

TLRs:

toll-like receptors

RIPK1:

receptor-interacting protein kinase 1

MLKL:

mixed lineage kinase domain-like protein

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  1. Laboratory of Neurodegenerative Diseases, Center for Biomedicine, Universidad Mayor, Temuco, Chile

    Elizabeth Carrazana & Natalia Salvadores

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  1. Elizabeth Carrazana
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N.S. conceptually designed the work. E.C. and N.S. wrote the manuscript. E.C. made the illustration. N.S. edited the manuscript and figure. Both authors read and approved the manuscript.

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Carrazana, E., Salvadores, N. Therapeutic implications of necroptosis activation in Alzheimer´s disease. Alz Res Therapy 16, 275 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13195-024-01649-8

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Alzheimer's Research & Therapy

ISSN: 1758-9193