Microglial Senescence and Neurodegenerative Diseases

Microglial senescence is a cellular state characterized by irreversible cell cycle arrest, altered morphology, and a pro-inflammatory secretory profile, typically resulting from cumulative stressors such as oxidative damage, chronic inflammation, or aging. Senescent microglia exhibit impaired phagocytic function and contribute to neuroinflammatory and neurodegenerative processes.

Microglial senescence is a notable feature of both normal aging and neurodegenerative diseases, though its manifestation and impact differ between these two conditions. Studies in rodents has shown that with aging, there is an accumulation of senescent microglia, characterized by structural changes, such as de-ramification and cytoplasmic fragmentation (Ng, 2023). In naturally aged mice, microglia exhibit diminished phagocytic activity and reduced motility, which may contribute to cognitive decline. Additionally, both human and murine aging microglia adopt a proinflammatory phenotype, leading to prolonged inflammation that negatively affects neuronal health (Ng, 2023).

In contrast, microglial senescence in neurodegenerative diseases assumes a more pathological role. In proteinopathies, such as AD and PD, there is an increase in microglia that exhibit a dystrophic appearance, alongside the presence of DAM (Ng, 2023). In murine models of these diseases, a downregulation of genes responsible for maintaining microglial homeostasis is observed, signaling a loss of the microglial cells’ normal functions. While a similar loss of homeostasis occurs during normal aging, its heightened prevalence in neurodegenerative diseases suggests that aging may increase susceptibility to these diseases. Furthermore, senescent microglia play a central role in the progression of neurodegenerative diseases by intensifying inflammation and worsening neurodegeneration (Ng, 2023). Thus, while microglial senescence occurs in both normal aging and neurodegenerative diseases, it has a far more damaging effect in the latter, directly accelerating disease progression.

Beyond AD and PD, microglial senescence is also involved in a range of other neurodegenerative disorders, such as:

• Multiple Sclerosis (MS)
  • In a mouse model of MS, microglia positive for p16INK4a were found to be highly expressed in DAM, and knocking out p16^INK4a in microglia reduced paralysis, suggesting that targeting microglial senescence could be a potential therapeutic strategy for MS (Matsudaira, 2023).
• Frontotemporal Lobar Degeneration (FTLD) & Amyotrophic Lateral Sclerosis (ALS)
  • Mice with a deficiency of microglial TDP-43, a protein implicated in FTLD and ALS, show enhanced phagocytosis of amyloid-β, indicating that microglial TDP-43 plays a role in regulating phagocytic activity (Paolicelli, 2017). This finding suggests that impaired TDP-43 function could contribute to microglial dysfunction and potentially induce senescence, which might accelerate the progression of neurodegenerative diseases, like ALS and FTLD.
  • In a rat model ALS, senescent microglia were shown to appear as the disease progressed toward paralysis (Trias, 2019).

These findings highlight the role of microglial senescence in MS, FTLD, and ALS, underscoring its potential as a target for therapeutic interventions in various neurological disorders.

Developing therapies aimed at targeting senescent microglia presents several challenges:

• Absence of specific biomarkers that can reliably identify senescent microglia, which necessitates the use of a multi-marker approach
• Diversity of the microglial senescent phenotype, making it difficult to define and classify senescence accurately
• Translating findings from preclinical studies to human clinical trials

Despite these challenges, senolytic drugs, which selectively target and eliminate senescent cells, have shown promising results in increasing lifespan and improving quality of life in mouse models (Lau, 2023). Ongoing clinical trials are investigating the potential of senolytics, such as dasatinib and quercetin for AD, offering hope that these treatments may overcome some of the challenges associated with targeting senescent microglia in neurodegenerative diseases (NCT04785300, NCT04685590).

Senescent and dystrophic microglia both undergo similar morphological changes as part of the aging process. However, there is ongoing debate about whether these two terms describe a single state or distinct conditions. Evidence suggests that they are separate states, with senescent microglia exhibiting additional features, such as irreversible cell cycle arrest and the development of a SASP (Neumann, 2023). Research has shown that dystrophic microglia in the human brain do not express the typical markers of senescence, indicating that dystrophy might not represent a senescent state (Neumann, 2023). However, dystrophic microglia do display ferritin expression, which may eventually contribute to the onset of senescence (Neumann, 2023; Samuel Olajide, 2024). Therefore, while senescent and dystrophic microglia share some morphological similarities, evidence indicates that they are distinct cellular states (Neumann, 2023).

Senescent microglia exhibit reduced capacity for debris clearance, altered cytokine profiles (e.g. increased TNF-α, IL-6, IL-1β), and a shift toward a chronically activated, neurotoxic state. This dysfunction contributes to neuronal damage and progression of neurodegenerative diseases such as AD, PD, MS, FTLD, and ALS. 

Emerging strategies include senolytic agents that selectively eliminate senescent cells, and interventions aimed at restoring mitochondrial function or reducing oxidative stress. However, most approaches are still in preclinical stages and require further validation in neurodegenerative models. 

Angelova, D.M., Brown, D.R. Microglia and the aging brain: are senescent microglia the key to neurodegeneration? J. Neurochem., 151: 676-688, 2019; doi: 10.1111/jnc.14860

Bussian, T.J., Aziz, A., Meyer, C.F., Swenson, B.L., van Deursen, J.M., Baker, D.J. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature, 562: 578-582, 2018; doi: 10.1038/s41586-018-0543-y

Chaib, S., Tchkonia, T., Kirkland, J.L. Cellular senescence and senolytics: the path to the clinic. Nat. Med., 28: 1556-1568, 2022; doi: 10.1038/s41591-022-01923-y

Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., Amit, I. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell, 173: 1073-1081, 2018; doi: 10.1016/j.cell.2018.05.003

Greenwood, E.K., Brown, D.R. Senescent microglia: the key to the ageing brain? Int. J. Mol. Sci., 22: 4402, 2021; doi: 10.3390/ijms22094402

Hong, B., Ohtake, Y., Itokazu, T., Yamashita, T. Glial senescence enhances α-synuclein pathology owing to its insufficient clearance caused by autophagy dysfunction. Cell Death Discov., 10: 50, 2024; doi: 10.1038/s41420-024-01816-8

Hu, Y., Fryatt, G.L., Ghorbani, M., Obst, J., Menassa, D.A., Martin-Estebane, M., Muntslag, T.A.O., Olmos-Alonso, A., Guerrero-Carrasco, M., Thomas, D., Cragg, M.S., Gomez-Nicola, D. Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology. Cell Rep., 35: 109228, 2021; doi: 10.1016/j.celrep.2021.109228

Karabag, D., Scheiblich, H., Griep, A., Santarelli, F., Schwartz, S., Heneka, M.T., Ising, C. Characterizing microglial senescence: tau as a key player. J. Neurochem., 166: 517-533, 2023; doi: 10.1111/jnc.15866

Lau, V., Ramer, L., Tremblay, M.È. An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer's disease. Nat. Commun.,14: 1670, 2023; doi: 10.1038/s41467-023-37304-3

Malvaso, A., Gatti, A., Negro, G., Calatozzolo, C., Medici, V., Poloni, T.E. Microglial senescence and activation in healthy aging and Alzheimer's disease: systematic review and neuropathological scoring. Cells, 12: 2824, 2023; doi: 10.3390/cells12242824

Matsudaira, T., Nakano, S., Konishi, Y., Kawamoto, S., Uemura, K., Kondo, T., Sakurai, K., Ozawa, T., Hikida, T., Komine, O., Yamanaka, K., Fujita, Y., Yamashita, T., Matsumoto, T., Hara, E. Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype. Commun. Biol., 6: 665, 2023; doi: 10.1038/s42003-023-05027-2

Miao, J., Ma, H., Yang, Y., Liao, Y., Lin, C., Zheng, J., Yu, M., Lan, J. Microglia in Alzheimer's disease: pathogenesis, mechanisms, and therapeutic potentials. Front. Aging Neurosci., 15:1201982, 2023; doi: 10.3389/fnagi.2023.1201982

Neumann, P., Lenz, D.E., Streit, W.J., Bechmann, I. Is microglial dystrophy a form of cellular senescence? an analysis of senescence markers in the aged human brain. Glia. 71: 377-390, 2023; doi: 10.1002/glia.24282

Ng, P.Y., McNeely, T.L., Baker, D.J. Untangling senescent and damage-associated microglia in the aging and diseased brain. FEBS J., 290: 1326-1339, 2023; doi: 10.1111/febs.16315

Paolicelli, R.C., Jawaid, A., Henstridge, C.M., Valeri, A., Merlini, M., Robinson, J.L., Lee, E.B., Rose, J., Appel, S., Lee, V.M., Trojanowski, J.Q., Spires-Jones, T., Schulz, P.E., Rajendran, L. TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron, 95: 297-308.e6, 2017; doi: 10.1016/j.neuron.2017.05.037

Paolicelli, R.C., Sierra, A., Stevens, B., Tremblay, M.E., Aguzzi, A., Ajami, B., Amit, I., Audinat, E., Bechmann, I., Bennett, M., Bennett, F., Bessis, A., Biber, K., Bilbo, S., Blurton-Jones, M., Boddeke, E., Brites, D., Brône, B., Brown, G.C., Butovsky, O., … Wyss-Coray, T. Microglia states and nomenclature: a field at its crossroads. Neuron, 110: 3458-3483, 2022; doi: 10.1016/j.neuron.2022.10.020

Rim, C., You, M.J., Nahm, M., Kwon, M.S. Emerging role of senescent microglia in brain aging-related neurodegenerative diseases. Transl. Neurodegener., 13: 10, 2024; doi: 10.1186/s40035-024-00402-3

Samuel Olajide, T., Oyerinde, T.O., Omotosho, O.I., Okeowo, O.M., Olajide, O.J., Ijomone, O.M. Microglial senescence in neurodegeneration: insights, implications, and therapeutic opportunities. Neuroprotection, 2: 182-195, 2024; doi: 10.1002/nep3.56

Shaerzadeh, F., Phan, L., Miller, D., Dacquel, M., Hachmeister, W., Hansen, C., Bechtle, A., Tu, D., Martcheva, M., Foster, T.C., Kumar, A., Streit, W.J., Khoshbouei, H. Microglia senescence occurs in both substantia nigra and ventral tegmental area. Glia. 68: 2228-2245, 2020; doi: 10.1002/glia.23834

Trias, E., Beilby, P.R., Kovacs, M., Ibarburu, S., Varela, V., Barreto-Núñez, R., Bradford, S.C., Beckman, J.S., Barbeito, L. Emergence of microglia bearing senescence markers during paralysis progression in a rat model of inherited ALS. Front. Aging Neurosci., 11: 42, 2019; doi: 10.3389/fnagi.2019.00042

Alpha-Synuclein: a presynaptic neuronal protein that is genetically and neuropathologically associated with Parkinson's disease (PD).

Alzheimer's Disease: a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes. It is associated with the accumulation of amyloid-beta plaques and tau tangles in the brain, and loss of neurons and synapses in the cerebral cortex and subcortical regions.

Amyloid-beta (Aβ): a peptide derived from the amyloid precursor protein (APP) that can aggregate to form plaques.

Amyotrophic Lateral Sclerosis (ALS): also known as Lou Gehrig's disease, it is the most common form of motor neuron disease and affects the upper and lower motor neurons. This fatal neuromuscular disease is characterized by progressive weakness of the muscles required to move, speak, eat, and breathe.

Autophagy: derived from the Greek word meaning “self-eating”, autophagy was coined by Belgian biochemist Christian de Duve to describe a lysosomal degradative process within cells for the removal and recycling of cellular debris.

Disease-Associated Microglia (DAM): a subset of microglia with a specific transcriptional signature – conserved in human and mice – thought to play an important role in neurodegenerative disorders. Originally discovered in AD, but also appear to be present in other neurodegenerative diseases (Deczkowska, 2018). Whether they are more accurately described as one signature across diseases or distinct signatures in distinct diseases is still under investigation (Paolicelli, 2022).

Lewy bodies: large deposits of alpha-synuclein that accumulate within neurons. These clumps are hallmark of Parkinson’s disease.

Microglia: one of the neuroglial cell types present in the brain and spinal cord. Constituting approximately 10-15% of the total cellular population in the brain, microglial cells function as the primary immune cells of the central nervous system. These cells are essential for maintaining homeostasis, clearing cellular debris, and providing critical support functions within the brain.

Misfolded proteins: 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).

Multiple Sclerosis (MS): the most commonly demyelinating disease of the central nervous system (CNS); MS is an immune-mediated disease, involving T cell, B cells, microglia, and macrophages, and characterized by inflammation, demyelination, axonal injury, and neurodegeneration.

Neuritic Plaques: amyloid-beta plaque containing dystrophic neurites (degenerating axons and dendrites).

Neuroinflammation: an inflammatory response within the central nervous system (CNS), primarily involving the activation of microglia and astrocytes. This process can be triggered by various factors, including infections, traumatic brain injury, toxic metabolites, and autoimmune diseases.  

Parkinson's Disease (PD): 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.

Proteinopathies: also called protein conformational disorders, or protein misfolding diseases, are a group of diseases in which specific proteins become structurally abnormal, can become toxic or lose their normal function.

Protein Aggregates: clusters of misfolded proteins that clump together inside or around cells like tangled balls of yarn.

Senescent-Associated Secretory Phenotype (SASP): a profile of senescent cells characterized by the secretion of factors, including interleukins, chemokines, inflammatory cytokines, proteases, and growth factors. SASP accumulates over time with aging and in age-related pathologies.  

Senescent Microglia: 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.

Tau: 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).

Transactive response DNA binding protein of 43 kDa (TDP-43): a highly conserved nuclear RNA/DNA-binding protein encoded by the TARDBP gene involved in the regulation of RNA processing.