The human brain, essential for numerous functions, is increasingly vulnerable to neurological diseases. These conditions present significant clinical challenges, often involving immune mechanisms mediated by brain cells like microglia and astrocytes. The following sections explore the role of these immune cells in the development and progression of selected NDs, highlighting their immune mechanisms.
Immune responses in neurodegenerative diseases
Brain diseases such as NDs involve complex immune responses within the CNS, driven by cortical atrophy and abnormal protein accumulation that stress neurons and lead to their degeneration. This neuronal damage triggers an innate immune response, with microglia and astrocytes undergoing reactive changes to manage diseased neurons and contain abnormal proteins.253,254 Additionally, adaptive immune cells, such as CD8+ T cells, CD4+ T cells, and B cells, are recruited, shaping the neuroinflammatory environment to either support neuronal health or exacerbate disease progression.255–257
In AD, characterized by amyloid-β plaques and neurofibrillary tangles, microglia initially attempt to clear Aβ plaques but become chronically activated, leading to sustained inflammation, neurotoxicity, and synapse loss.258 This persistent activation not only fails to clear Aβ efficiently but also exacerbates neuronal damage. CD8+ T cells may worsen neurodegeneration by directly interacting with compromised neurons, while CD4+ T cells modulate microglial activity, influencing the balance between neuroprotection and neuroinflammation.259,260 B cells play a dual role by producing antibodies against abnormal proteins, potentially aiding clearance but also exacerbating inflammation through cytokine release.260–262
Microglial cells, the brain’s primary immune responders, exhibit distinct activation states known as M1 and M2 phenotypes, which play critical roles in neuroinflammatory diseases such as AD and MS.3–7 The M1 phenotype, associated with pro-inflammatory responses, is activated by stimuli such as lipopolysaccharides or pro-inflammatory cytokines. M1 microglia release cytokines like TNF-α, IL-1β, and IL-6, along with ROS, which contribute to neurodegeneration. In AD, M1 microglia exacerbate Aβ plaque formation and tau phosphorylation, leading to increased neuronal damage and cognitive decline. Similarly, in MS, M1 microglia promote autoimmune responses and myelin damage, contributing to demyelination and neurodegeneration.263,264
In contrast, the M2 phenotype is generally associated with anti-inflammatory and repair functions. Activated by signals such as IL-4 and IL-13, M2 microglia secrete anti-inflammatory cytokines such as IL-10 and transforming growth factor-β (TGF- β) and are involved in tissue repair and debris clearance.265 In AD, M2 microglia help clear Aβ plaques and promote tissue repair, although their functionality may be impaired during chronic inflammation.107,108 In MS, M2 microglia contribute to remyelination and repair processes, though their effects are often overshadowed by the dominant M1 response, especially during acute disease phases.266,267
Recent insights suggest that modulating the balance between M1 and M2 microglial states could offer therapeutic benefits. Research indicates that shifting the microglial response towards the M2 phenotype may reduce Aβ plaque accumulation in AD and improve cognitive outcomes.268,269
Similarly, in MS, targeting pathways that promote M2 polarization or inhibit M1 activation shows promise for slowing disease progression and enhancing repair.270 Understanding the dynamics of these microglial phenotypes provides potential strategies for managing neuroinflammatory diseases by balancing their roles in inflammation and repair.
On the other hand, astrocytic dysfunction plays a critical role in the progression of brain diseases, particularly in AD. Astrocytes are essential for maintaining brain homeostasis, including the clearance of Aβ through processes such as phagocytosis and the release of Aβ-degrading enzymes. In AD, astrocytes often exhibit impaired functionality, leading to a failure to clear Aβ. This accumulation of Aβ contributes to the formation of neurotoxic plaques and disrupts neuronal function.113,116
Recent research has uncovered several mechanisms underlying astrocytic dysfunction in AD. Studies have shown that astrocytes in AD brains exhibit reduced expression of key receptors and transporters involved in Aβ clearance, such as low-density lipoprotein receptor-related protein 1 and aquaporin-4 channels, which are part of the glymphatic system.271,272 This impairment compromises their ability to effectively remove Aβ from the extracellular space. Additionally, oxidative stress and chronic inflammation further exacerbate astrocytic dysfunction by damaging cellular components and impairing their ability to maintain neurovascular integrity.273,274
Research has also explored the impact of impaired astrocytic clearance on disease progression. For example, studies have demonstrated that genetic or pharmacological restoration of astrocytic function can reduce Aβ levels and alleviate cognitive deficits in animal models of AD.275,276 Activation of astrocytic signaling pathways, such as NF-κB and peroxisome proliferator-activated receptor-γ (PPAR-γ), has been shown to enhance Aβ clearance and reduce plaque burden.38–44
Furthermore, research into the role of the glymphatic system has revealed that disruptions in cerebrospinal fluid (CSF) flow and waste clearance, due to dysfunctional astrocytes, significantly contribute to disease progression.277
Overall, the dysfunction of astrocytes in AD, particularly their failure to clear Aβ, is a key driver of disease progression. Recent research underscores the importance of restoring astrocytic function as a potential therapeutic strategy, aiming to enhance Aβ clearance and mitigate the neurodegenerative processes associated with AD.
Interestingly, research has revealed significant sex-based differences in the structure and function of microglia. These variations can affect how microglia respond to injuries, diseases, and changes in brain function. Male and female microglia may differ in terms of density, shape, and activity levels, which impacts their susceptibility to neurological disorders and influences the overall immune response in the brain.278–280 Gaining insights into these sex-specific differences is essential for developing more tailored and effective treatments for neurological conditions.
The higher incidence of AD in women compared to men is strongly associated with sex-specific differences in microglia, the brain’s primary immune cells. Studies show that microglia in females and males react differently to the pathological changes seen in AD.281–283
One key factor is the inflammatory response. Research suggests that female microglia may exhibit more pronounced inflammatory reactions than their male counterparts. This heightened response could accelerate neurodegeneration and contribute to the higher incidence of Alzheimer’s in women.284
Hormonal influences also play a significant role. Estrogen, more prevalent in females, can affect microglial function and inflammation. Fluctuations in estrogen levels, especially during menopause, may impact how microglia interact with Aβ plaques and tau tangles, both of which are central to Alzheimer’s pathology.285,286
Genetic and epigenetic factors also contribute to these differences. Changes in genes associated with immune responses and neuroinflammation can alter microglial function, resulting in varied susceptibilities to AD between genders. Additionally, differences in microglial density and activity between males and females impact the efficiency of Aβ plaque clearance and the handling of neurotoxic conditions. These differences may help explain the increased vulnerability to AD observed in women.287,288
Understanding these sex-dependent differences in microglial structure and function is crucial for developing more targeted and effective approaches to prevent and treat AD in both men and women.32
Recent studies have shown that microglia play dual roles in AD.64,67 While traditionally viewed as contributors to neuroinflammation and plaque accumulation, recent evidence suggests that microglia are also crucial for clearing Aβ plaques and supporting neuronal health. New research using advanced imaging and genetic tools has revealed that microglial depletion can lead to increased Aβ plaque buildup and worsening cognitive deficits, but it may also alleviate inflammation in some contexts.202–204 This reflects the complex balance between the beneficial and detrimental aspects of microglial activity, which must be carefully considered.208,211
On the other hand, emerging data suggest that peripheral immune cells, such as T cells and monocytes, play a significant role in Alzheimer’s pathology. Studies have found that depleting peripheral immune cells can reduce systemic inflammation and alleviate some aspects of disease progression.289,290 However, the overall impact can be mixed, as removing these cells might disrupt essential immune functions and impair the brain’s ability to respond effectively to injury.
In PD, cognitive assessments often show that men perform worse than women.291 Specifically, males tend to struggle more with verbal fluency, inhibition, and processing speed. This cognitive decline in men is often more pronounced, affecting their ability to generate words, control impulsive responses, and process information quickly. These differences underscore the need for gender-specific approaches to understanding and addressing cognitive impairments in PD.292
As previously mentioned, variations in microglial density, morphology, and activity between males and females may influence the progression of NDs. Male microglia, in particular, may show less effective neuroinflammatory responses and compromised synaptic maintenance, which could contribute to the exacerbation of cognitive decline in men. This highlights the importance of considering sex-based differences in neuroinflammatory processes when developing targeted treatments for PD.
Additionally, in PD, there is growing evidence that T cells play a role in driving neuroinflammation and disease progression.293 T cells influence microglial polarization toward the pro-inflammatory M1 phenotype while suppressing the protective M2 phenotype.294,295 This dysregulation creates a neurotoxic environment that contributes to the degeneration of dopaminergic neurons, which is central to PD pathology. Understanding the interplay between T cells and microglia reveals potential therapeutic avenues for restoring immune balance and preserving neuronal integrity in PD.293–296
Furthermore, evidence suggests that individuals in the prodromal stage of PD, who are at a heightened risk of progressing to the disease, show elevated levels of alpha-synuclein antibodies.297 This suggests a potential involvement of B lymphocytes in PD progression. Although these antibodies are not found in early PD patients, their presence indicates a potential pathological role for alpha-synuclein antibodies.298
There is also speculation that these antibodies could be protective, aiding in the clearance of pathological proteins. Supporting this notion, a study by Li et al.299 demonstrated that certain alpha-synuclein antibodies derived from patients were capable of inhibiting the seeding of alpha-synuclein in vitro.
Moreover, B cells perform multiple functions beyond antibody production, including presenting antigens, regulating T cells and innate immune cells, producing cytokines, and maintaining subcapsular sinus macrophages. Considering the significant inflammation observed in both the CNS and the periphery in PD, it is likely that B lymphocytes contribute to the disease. Many of their effects are likely mediated through these various roles. Further research is needed to clarify the specific contributions of B lymphocytes to PD progression.
Additionally, recent research has provided new insights into the role of microglia in PD. While earlier studies suggested that microglial depletion could reduce neuroinflammation and improve motor symptoms, newer research indicates that microglial activity is also essential for responding to neuronal damage and supporting neuronal survival.300,301 This suggests that complete depletion of microglia might impair the brain’s repair mechanisms and exacerbate neurodegeneration. Therefore, targeted modulation of microglial activity, rather than total depletion, may be more beneficial.302
On the other hand, recent studies on peripheral immune cell depletion in PD models show that reducing the activity of these cells can decrease systemic inflammation and potentially slow disease progression.303,304
However, evidence also suggests that such depletion might disrupt normal immune surveillance and repair processes, potentially leading to adverse outcomes.305 This highlights the importance of balancing immune responses to support neuronal health while minimizing harmful effects.
These findings emphasize the complex, often context-dependent roles of immune cells in NDs, suggesting that therapeutic strategies must carefully target immune cell functions to balance their protective and harmful effects.
Targeting microglia and astrocytes in AD and PD requires advanced strategies to modulate their complex roles in neurodegeneration and inflammation. Several methods can be used to target microglia. Anti-inflammatory agents and immunomodulatory therapies aim to mitigate the detrimental effects of chronic inflammation by inhibiting the production of pro-inflammatory cytokines and ROS.306,307
Additionally, strategies to enhance plaque clearance involve developing pharmaceuticals or employing genetic techniques to boost microglial activity, which is essential for removing Aβ plaques and slowing AD progression. Targeting specific receptors, such as TREM2 (triggering receptor expressed on myeloid cells 2), has also been shown to improve microglial uptake of plaques and enhance neuroprotection. These approaches seek to balance the beneficial and harmful effects of microglial activity to better manage NDs.308,309
Similarly, strategies for modulating astrocytes focus on their reactive states. A1 astrocytes, which are neurotoxic, can be shifted toward a more protective A2 state using signaling pathway inhibitors or enhancers. Increasing the production or delivery of neurotrophic factors, such as BDNF and insulin-like growth factor 1, which are produced by A2 astrocytes, supports neuronal survival and repair.310,311
Additionally, targeting calcium signaling and astrocytic transport systems helps normalize astrocyte functions critical for maintaining synaptic health and ion balance. Efforts to reduce excessive astrogliosis aim to prevent astrocyte overactivation and scarring, which can further damage neurons.312,313
Combining these approaches while ensuring therapeutic specificity and evaluating long-term outcomes is crucial for developing effective treatments. By targeting both microglia and astrocytes, these strategies aim to address the multifaceted nature of neurodegenerative diseases, potentially improving cognitive function and slowing disease progression in AD and PD.
In AD and PD, the roles of immune cells evolve throughout disease progression, necessitating tailored therapeutic approaches at each stage. In the early stages of AD, microglia are initially activated to respond to Aβ plaques and tau pathology. Targeting these cells with anti-inflammatory agents can help manage inflammation and prevent excessive plaque buildup, potentially delaying disease onset.314
As AD progresses to the intermediate stage, chronic inflammation becomes more pronounced, and the balance between protective and harmful microglial responses can shift. At this point, therapies should aim to reduce persistent inflammation and promote neuroprotection by modulating both microglial activity and astrocyte states, particularly by shifting neurotoxic A1 astrocytes to a more protective A2 state.
In the late stages of AD, where extensive neuronal loss and severe inflammation are present, treatments may focus on controlling chronic inflammation and preserving the remaining neurons, potentially using advanced immunomodulatory therapies and novel approaches like gene and cell-based therapies.315,316
In PD, therapeutic strategies also adapt to the disease stage. During the early stage, localized inflammation in the substantia nigra, where dopaminergic neurons are initially compromised, can be managed by targeting microglial activation with anti-inflammatory drugs to slow neuronal loss.
As the disease progresses to the intermediate stage, inflammation becomes more widespread, involving both central and peripheral immune cells. At this point, combined therapies are necessary to address the contributions of both microglia and astrocytes to neurodegeneration, aiming to reduce sustained inflammation and protect neuronal function.
In the late stage, characterized by significant dopaminergic neuron loss and severe motor symptoms, the focus shifts to managing chronic inflammation and supporting the remaining neurons. Advanced therapies and innovative treatments may be employed to enhance patient quality of life and slow disease progression. Adapting treatments to these stage-specific immune cell dynamics is essential for effective management and improved therapeutic outcomes in PD.317,318
Last but not least, emerging evidence suggests a role for B cells in PD, particularly through their potential involvement in alpha-synuclein pathology. Elevated levels of alpha-synuclein antibodies in prodromal PD stages indicate B cell activation, though their exact role—whether protective or pathogenic—remains unclear. B cells contribute to PD pathogenesis through diverse functions beyond antibody production, including antigen presentation, cytokine modulation, and interaction with other immune cells in both CNS and peripheral inflammation contexts.319–323