TNF-α (TNF-alpha) & Microglia in Neurodegenerative Diseases

Q: Which biomarkers can be used to track neuroinflammation in vivo?

Tracking neuroinflammation in vivo in humans is challenging because pro-inflammatory cytokines like TNF-α are present in low concentrations in the blood and CSF. While cytokines are key drivers of neuroinflammation in diseases such as AD, PD, and ALS, their detection in clinical settings requires highly sensitive methods that are often invasive or impractical for routine use. As a promising alternative, advanced imaging techniques like positron emission tomography (PET) are increasingly employed to monitor neuroinflammation. PET scans using radiotracers, such as 11C-PK11195 and 18F-DPA-714, can detect microglial reactivity, a hallmark of neuroinflammation in the brain. This non-invasive imaging approach offers an effective way to track neuroinflammation in vivo and may provide valuable insights into the progression of neurodegenerative diseases (Corcia, 2012; Tondo, 2020).

Last Updated: March 28, 2025

Authors: Alexa Brown, Ph.D. and Barry J. Bedell, M.D., Ph.D.

This resource describes:

What is the role of TNF-α in the central nervous system (CNS)?

Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine that plays a crucial role in regulating inflammation and immune responses. In the central nervous system (CNS), TNF-α has a dual function, contributing positively under healthy conditions, but potentially causing harm when dysregulated in diseased states.

Under homeostatic conditions, TNF-α supports:

Neuroplasticity
Myelination
Tissue repair

However, elevated TNF-α levels can lead to:

Excitotoxity
Chronic inflammation
Breakdown of the blood-brain barrier (BBB)

TNF-α exists in both soluble and transmembrane forms, and acts through two main receptors:

TNF receptor type-1 (TNFR1)
TNF receptor type-2 (TNFR2)

Its expression is tightly regulated by various transcription factors, notably nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). When activated, NF-κB:

Promotes TNF-α production
Triggers the expression of other pro-inflammatory cytokines, such as IL-6 and IL-1β
Creates a positive feedback loop that sustains and amplifies the inflammatory response (Gonzalez Caldito, 2023).

See: What is NF-κB (Nuclear Factor Kappa B)?

The main source of TNF-α during neuroinflammation is microglia, the resident immune cells of the CNS. Astrocytes can also contribute to its release under certain conditions (Olmos, 2014).

See: TNF-α & Astrocytes in Neurodegenerative Diseases

In the context of neurodegenerative diseases, microglial reactivity, along with other states like microglial senescence and the senescence-associated secretory phenotype (SASP), drives the chronic overproduction of TNF-α. Additional inflammatory cytokines, such as interferon-gamma (IFN-ϒ), further stimulate microglia, reinforcing the inflammatory cycle. This sustained neuroinflammatory state is implicated in the progression of diseases such as:

Alzheimer's disease (AD)
Parkinson’s disease (PD)
Amyotrophic lateral sclerosis (ALS)

Therapeutic strategies targeting TNF-α have shown potential in treating CNS autoimmune diseases, and may offer a way to modify the neuropathological features of neurodegenerative diseases (Torres-Acosta, 2020; Gonzalez Caldito, 2023). However, such treatments are not without complications. In some cases, anti-TNF-α therapies have exacerbated conditions like multiple sclerosis (MS) (Fresegna, 2020). This paradox likely stems from the dual role of TNF-α: it can be both neurotoxic and neuroprotective depending on context and receptor involvement.

Ongoing research into the temporal dynamics of TNF-α expression, especially in early versus late stages of disease progression, may offer crucial insights (Guidotti, 2021). Understanding when and how to modulate TNF-α could determine whether such interventions are helpful or harmful.

TNF-α-NF-κB Feedback Loop in Inflammation.
Binding of soluble TNF-α to TNFR1 activates NF-κB, which enters the nucleus and promotes transcription of proinflammatory cytokines like IL-6, IL-1β, and TNF-α. This creates a positive feedback loop that amplifies inflammation. Sustained TNF-α signaling can cause tissue damage and excitotoxity, contributing to chronic inflammation in neurodegenerative diseases.

How is TNF-α implicated in neurodegenerative diseases such as AD, PD, and ALS?

Alzheimer's Disease (AD)
AD is a neurodegenerative disease marked by progressive cognitive decline, memory impairment, and the accumulation of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. Increasing evidence suggests that inflammatory cytokines, including TNF-α, play a pivotal role in AD pathology.

In patients with AD, elevated levels of cytokines - notably TNF-α, IL-1β, and IL-6 - have been detected in:

The blood
Cerebrospinal fluid (CSF)

However, findings are not always consistent, likely due to differences in disease stage (Brosseron, 2014).

Despite these inconsistencies, several trends have emerged:

Cytokine levels (particularly TNF-α) tend to increase as AD progresses
Cytokine-to-receptor ratios may serve as better biomarkers than cytokine levels alone
Elevated cytokines may reflect a higher risk of developing AD

A major contributor to this inflammatory environment is microglial dysfunction. In AD models with Aβ accumulation:

Aged microglia display reduced phagocytic ability
There is increased TNF-α and IL-1β expression
Microglia reactivity promotes a feedback loop:
- Aβ plaques activate microglia
- Microglia release TNF-α
- TNF-α intensifies inflammation and neuronal damage
- Damage leads to further Aβ accumulation

This cycle perpetuates the neurodegenerative process, linking inflammation directly to disease progression (Hickman, 2008).

Therapeutic efforts to inhibit TNF-α in AD have shown mixed results:

Etanercept (TNF-α inhibitor) via perispinal administration showed cognitive improvements in small open-label trials (Tobinick, 2008)
Peripheral administration of etanercept showed no significant benefit (Butchart, 2015)
A Phase 1b trial for XPro1595, targeting soluble TNF-α, has shown promise (NCT03943264)

This shift toward selectively inhibiting soluble TNF-α offers a more targeted strategy with potentially fewer side effects.

Inflammatory Feedback Loop in Alzheimer's Disease.
In Alzheimer's disease, Aβ plaques and tau tangles activate microglia, triggering release of pro-inflammatory cytokines like TNF-α. This amplifies neuroinflammation and neurodegeneration. At the same time, impaired microglial clearance leads to further accumulation of toxic proteins, reinforcing the cycle and accelerating disease progression.

Parkinson’s Disease (PD)
PD is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), resulting in hallmark motor symptoms such as tremor, rigidity, and bradykinesia. It also includes non-motor symptoms like cognitive impairment and sleep disturbances.

Chronic neuroinflammation is a key component of PD pathology. Evidence includes:

Microglial reactivity and elevated TNF-α in postmortem SN samples and serum (Collins, 2012)
Increased TNF-α in serum and CSF in PD animal models
Presence of TNFR1 on dopaminergic neurons in the SNc

In PD patients, increased activation of NF-κB, a transcription factor for pro-inflammatory genes, has also been observed (Mogi, 2007). This activation reinforces cytokine expression and microglial reactivity.

Therapeutic studies in animal models support the benefit of TNF-α inhibition:

Thalidomide, a TNF-α synthesis inhibitor, protected against MPTP-induced dopamine depletion (Ferger, 2004)
TNF-α-deficient mice showed reduced striatal dopamine loss
XENP345, a TNF-α blocker, reduced dopaminergic neuron death (McCoy, 2006)

These findings highlight TNF-α as a potential therapeutic target to modulate inflammation and slow disease progression in PD.

Amyotrophic Lateral Sclerosis (ALS)
ALS is a progressive neurodegenerative disease that primarily targets motor neurons, leading to muscle weakness, difficulty speaking and swallowing, spasticity, paralysis, and eventual respiratory failure.

Neuroinflammation contributes significantly to disease progression, with elevated TNF-α levels observed in:

Plasma and serum of ALS patients
Animal models, particularly the superoxide dismutase 1 (SOD1) transgenic mouse (Olmos, 2014; Vu, 2017)

In these models:

NF-κB activation in spinal microglia is consistently observed (Frakes, 2014)

However, the role of TNF-α in ALS is more complex. Gene knockout studies in SOD1 model (removing TNF-α) did not significantly alter disease course, suggesting that while TNF-α may contribute to inflammation, it is not the primary driver of motor neuron loss in some contexts (Gowing, 2006).

Despite this, TNF-α inhibition has shown benefits. Thalidomide and lenalidomide improved motor function and reduced motor neuron loss in SOD1 mice (Kiaei, 2006) However, a Phase 2 trial in humans found no clinical benefit and reported notable side effects (Stommel, 2009).

These mixed results underscore the importance of:

Timing: Early intervention may be more effective
Stage-specific targeting: TNF-α may play different roles at different points in disease progression (Guidotti, 2021)

In conclusion, TNF-α plays a central role in neuroinflammation and neurodegeneration across diseases like AD, PD, and ALS. Despite differences in their underlying mechanisms, inflammatory processes driven by TNF-α appear to be a common factor in disease progression. While therapies tarting TNF-α show promise in preclinical models, clinical results have been inconsistent, highlighting the need for a deeper understanding of TNF-α’s role. Future research should focus on refining targeted treatments that modulate TNF-α signaling, potentially offering therapies to slow or halt the progression of these neurodegenerative diseases.

What evidence suggests that modulating TNF-α may slow or prevent neurodegenerative diseases?

Given its pivotal role in driving neuroinflammation, TNF-α is central to the progression of many neurodegenerative diseases, including AD, PD, and ALS. Chronic elevation of TNF-α in the CNS leads to neuronal damage and toxic protein accumulation, which together contribute to disease progression. As such, modulating TNF-α has emerged as a promising strategy to slow or even halt the progression of these diseases.

Anti-TNF-α therapies, successful in treating a range of autoimmune and inflammatory diseases, have drawn attention for their potential in neurodegenerative diseases (Gonzalez Caldito, 2023). Drugs such as etanercept (Enbrel®) and inﬂiximab (Remicade®), widely used in treating conditions like rheumatoid arthritis and other peripheral inflammatory diseases, have limited effectiveness in CNS disorders due to poor BBB penetration (Decourt, 2017). Other TNF-α inhibitors face similar challenges in accessing the CNS:

Adalimumab (Humira®)
Golimumab (Simponi®)
Certolizumab pegol (Cimzia®)

This challenge in TNF-α inhibition in CNS diseases is compounded by the risk of serious side effects, including:

Increased susceptibility to infections
Risk of demyelinating diseases
Potential worsening of diseases like MS

For example, in MS, treatments like lenercept have worsened disease outcomes (Maguire, 2021). The dual roles of TNF-α in neuroprotection and inflammation underscore the need for more selective targeting. Research on TNFR1 and TNFR2 has highlighted that selectively targeting TNFR1, while sparing TNFR2, may offer a safer and more effective approach for treating MS (Fresegna, 2020).

In response to these limitations, development of selective TNF-α inhibitors that specifically target TNFR1 for CNS use, such as atrosab and atrosimab, have demonstrated promising results in preclinical models of neuroinflammation, such as experimental autoimmune encephalomyelitis (EAE) (Richter, 2021). Similarly, a Phase 1b trial for XPro1595, a TNF-α inhibitor selective for soluble TNF-α has shown promising results in AD (NCT03943264). These therapies aim to offer a more targeted approach, improving safety and efficacy for neurodegenerative diseases.

While preclinical findings are promising, further clinical trials are necessary to establish the safety and effectiveness of these selective TNF-α blockers in humans. These studies will be crucial for determining whether these therapies can provide benefits for patients with neurodegenerative diseases. As research continues, the development of TNF-α therapies tailored for the CNS may offer an important approach to slowing or preventing neurodegeneration, improving outcomes for patients and advancing the field of neuroinflammation treatment (Decourt, 2017; Hampel, 2020; Zahedipour, 2022).

Our team would be happy to answer any questions about the function of TNF-α in microglia and its contribution to neurodegenerative diseases or provide specific information about the AD, ALS, and PD models we use for therapeutic efficacy studies.

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FAQs

What is TNF-α?

What makes TNFR1 and TNFR2 different, and why is the distinction important for therapy?

Why does TNF-α have both protective and harmful effects in the brain?

TNF-α exerts context-dependent effects in the CNS. Under physiological conditions, it supports neuroplasticity, synaptic scaling, and tissue homeostasis. However, in pathological states, elevated or sustained TNF-α expression promotes excitotoxicity, blood-brain barrier disruption, chronic glial activation, and neuronal apoptosis. Its net effect depends on concentration, duration, receptor subtype, and disease context.

What is the role of TNF-α in multiple sclerosis (MS)?

TNF-α plays a significant role in the inflammatory processes that drive MS, contributing to the characteristic demyelination in the disease. Elevated levels of TNF-α are observed in the CSF of MS patients, with these levels correlating to the severity and progression of the disease (). Similarly, TNF-α is upregulated in the . In this model, the administration of TNF-α exacerbates disease progression (; ). However, the role of TNF-α in the pathogenesis of MS and EAE is complex. Contrary to expectations, studies have shown that TNF-α knockout mice develop EAE with equal or worse outcomes compared to wild-type mice (). Clinical studies of anti-TNF-α therapy in MS patients have similarly yielded disappointing results, with evidence indicating worsened disease outcomes following treatment (). One particularly notable trial found that MS patients receiving lenercept, a molecule designed to block TNF-α, experienced a higher frequency of relapses, earlier onset of symptoms, and more severe neurological deficits compared to those in the placebo group (). These results highlight the complex relationship between TNF-α and MS, suggesting that while TNF-α is a key player in inflammation, effective therapeutic strategies will require careful targeting to balance inflammation control with minimizing side effects.

What are the challenges of TNF-α inhibition in treating neurodegenerative diseases?

One of the main challenges of TNF-α inhibition in treating neurodegenerative diseases is the risk of serious side effects, particularly with non-selective inhibition. These side effects include an increased susceptibility to infections and demyelinating diseases, as well as exacerbation of diseases like MS (). Clinical trials have shown that anti-TNF-α therapy can worsen MS outcomes, suggesting that while TNF-α promotes inflammation, it also plays essential beneficial roles in the CNS. This dual role of TNF-α can partly be explained by the distinct functions of its receptors, TNFR1 and TNFR2 (; ). In MS, TNFR1 is linked to inflammation and tissue damage, while TNFR2 is involved in neuroprotection and repair (). Research indicates that selective blockade of TNFR1 can improve outcomes in the , while knocking out TNFR2 exacerbates disease progression (; ; ). In contrast, studies in ALS have reported different roles for TNFR1 and TNFR2, with TNFR1 mediating neuroprotective effects and TNFR2 associated with harmful effects and cell death (). These findings highlight the challenge of developing effective TNF-α therapies, as they must target specific receptors to balance inflammation control with neuroprotection.

Which biomarkers can be used to track neuroinflammation in vivo?

Tracking neuroinflammation in humans is challenging because pro-inflammatory cytokines like TNF-α are present in low concentrations in the blood and CSF. While cytokines are key drivers of neuroinflammation in diseases such as AD, PD, and ALS, their detection in clinical settings requires highly sensitive methods that are often invasive or impractical for routine use. As a promising alternative, advanced imaging techniques like positron emission tomography (PET) are increasingly employed to monitor neuroinflammation. PET scans using radiotracers, such as C-PK11195 and F-DPA-714, can detect microglial reactivity, a hallmark of neuroinflammation in the brain. This non-invasive imaging approach offers an effective way to track neuroinflammation and may provide valuable insights into the progression of neurodegenerative diseases (; ).

What are the key future directions for research on TNF-α as a therapeutic target in neurodegenerative diseases?

Future research on targeting TNF-α in neurodegenerative diseases should focus on developing selective, brain-penetrant inhibitors that target neuroinflammation while minimizing side effects. Current TNF-α inhibitors are often too broad, leading to unwanted effects. More targeted inhibitors could improve safety for CNS diseases. Another key area is understanding the distinct roles of TNF-α receptors, TNFR1 and TNFR2, which could enable more precise therapies targeting one receptor over the other. Lastly, exploring TNF-α’s role in a wider range of neurodegenerative diseases, such as Huntington’s disease (HD), frontotemporal dementia (FTD), and other tauopathies is essential. Understanding its impact in these diseases could lead to tailored treatment strategies for various neurodegenerative pathologies.

References

Hampel, H., Caraci, F., Cuello, A.C., Caruso, G., Nisticò, R., Corbo, M., Baldacci, F., Toschi, N., Garaci, F., Chiesa, P.A., Verdooner, S.R., Akman-Anderson, L., Hernández, F., Ávila, J., Emanuele, E., Valenzuela, P.L., Lucía, A., Watling, M., Imbimbo, B.P., Vergallo, A., Lista, S. A path toward precision medicine for neuroinflammatory mechanisms in Alzheimer's disease. , : 456, 2020;

Keywords

: the BBB is a highly selective semipermeable layer of endothelial cells between the circulatory system and the brain. This layer forms a barrier that protects the brain from harmful or unwanted substances in the blood. Increased BBB permeability can result from neurological diseases and traumatic injuries and can be visible with gadolinium scans. Increased BBB permeability is a key factor in MS lesion formation, allowing immune cells to enter the brain and cause inflammation.

a group of neurodegenerative disorders characterized by progressive damage to the frontal and/or temporal lobes of the brain. This damage leads to a variety of symptoms that can include changes in personality, behavior, and language abilities. FTD is distinct from other types of dementia, such as Alzheimer's disease, in that it often affects younger individuals (typically between the ages of 45 and 65) and presents with early and prominent changes in social behavior, executive function, and language, rather than memory loss. The three main subtypes of FTD are behavioral variant FTD (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), and semantic variant primary progressive aphasia (svPPA).

proteins are composed of linear chains of amino acids that must fold into a functional three-dimensional structure. When these chains fail to fold properly, the resulting proteins can adopt abnormal shapes. These proteins are typically insoluble, and disrupt normal cellular processes. The accumulation of misfolded proteins is closely linked with several neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic lateral sclerosis (ALS).

a neurodegenerative disease that is characterized by: (a) movement-related (motor) symptoms, including resting tremor, bradykinesia, rigidity, and postural instability, related to the loss of dopaminergic neurons in the substantia nigra; and (b) non-motor symptoms including anxiety, depression, apathy, hallucinations, constipation, orthostatic hypotension, sleep disorders, hyposmia/anosmia, and cognitive impairment.

microglial cells that have entered a state of irreversible cell cycle arrest, exhibiting cytorrhexis, process de-ramification, process swelling, and vacuolization. These cells also show reduced motility and phagocytosis, while secreting proinflammatory cytokines, increasing reactive oxygen species, and accumulating iron and ferritin. This senescent state contributes to neuroinflammation and is linked to aging and diseases, including neurodegenerative diseases.

a protein that plays a crucial role in maintaining the stability and function of neurons in the brain. It is predominantly found in neurons, where it stabilizes microtubules, which are part of the cell's cytoskeleton. Microtubules are essential for maintaining cell shape, enabling intracellular transport, and facilitating cellular division. Hyperphosphorylation of tau is evident in various neurodegenerative diseases, where the abnormally phosphorylated molecules lead to the detachment of tau from the microtubules. These detached tau proteins can aggregate to form insoluble fibrils, known as neurofibrillary tangles. Diseases impacted by tau aggregation are called tauopathies, and include Alzheimer's disease, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and corticobasal degeneration (CBD).

TNF-α (TNF-alpha) & Microglia in Neurodegenerative Diseases

An overview of the function of tumor necrosis factor-alpha (TNF-α) in microglia and its contribution to the progression of neurodegeneration.

What is the role of TNF-α in the central nervous system (CNS)?

How is TNF-α implicated in neurodegenerative diseases such as AD, PD, and ALS?

What evidence suggests that modulating TNF-α may slow or prevent neurodegenerative diseases?

Discover more about our Neurodegenerative Diseases Models

ALS Models

Alzheimer's Disease Models

Parkinson's Disease Models

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