Implicating neuroinflammation in hippocampus, prefrontal cortex and amygdala with cognitive deficit: a narrative review

Recovery from functional, cognitive and biochemical disorders due to neuroinflammation might become easier by understanding the role of cells of the immune system, mechanisms and duration of the process (Healy et al 2022). The four hallmark characteristics of neuroinflammation include increased proinflammatory cytokines, activation of glial cells, infiltration of peripheral immune cells and tissue damage (Mittli 2023; Estes and McAllister 2014). When the homeostasis of the brain is disturbed by various tissue insults, those factors which regulate inflammation get activated causing an acute reaction, in order to initiate the healing process. In the initial phase, this protective mechanism is facilitated by glial activation, which is stimulated by external as well as internal triggering factors (Leyane et al 2022; Lam et al 2021). On the other hand, if damaging factors strike repeatedly the acute inflammatory response of the brain becomes chronic, accelerating glial cell activation, eventually resulting in tissue fragmentation and degeneration. The positive feedback loop gets converted into a negative loop during chronic neuroinflammation, wherein the pro-inflammatory cytokines, ROS and RNS (reactive nitrogen species) are released in large number, and they further accelerate glial activation, leading to excessive level of inflammatory mediators (Lecca et al 2022). This escalates the rate of neuroinflammation by further increasing the infiltration of immune cells through the blood–brain-barrier. Prolonged activation of microglia, associated with abnormal protein aggregation, mitochondrial damage, axonal transport abnormalities, and neuronal apoptosis facilitate neurodegeneration, leading to impaired neuronal function. Microglia and astrocytes generate cytokines and chemokines, which are taken up by the active components of the neuroinflammatory process (Zang et al 2022). Mainly elderly people suffer from neurodegenerative changes because the major drawback of human aging is increased release of inflammatory cytokines, like IL-1 & 6 as well as TNF-α. These cytokines are directly linked to compromising ROS elimination mechanisms resulting in oxidative stress and stimulation of the major inflammatory response activator NFκB (Teleanu et al 2022). This explains the reason for persistent neuroinflammation which is the common feature in individuals with age-related neurodegenerative diseases.

Prolonged peripheral inflammation in the peripheral organs due to various tissue insults like colitis, pancreatitis, gastritis etc. can cause systemic inflammation with simultaneous enhancement of proinflammatory mediators in circulation, that in due course can lead to neuroinflammation (Sun et al 2022). Moreover, peripheral inflammation can also result from an imbalance in gut microbiota and other chronic infections (Mou et al 2022; Furman et al 2019). Peripheral inflammation leading to neuroinflammation is mainly due to the breakdown of the BBB through which peripheral immune cells infiltrate into the brain (Huang et al 2021). Disruption of the BBB takes place through different mechanisms involving the cytokines, certain proteins at tight junctions (TJ), endothelial changes as well as oxidative stress.At tight junctions between the endothelial cells the TJ proteins get degraded or disorganized by the excessive proinflammatory cytokines in the circulatory system, and this in turn disrupts the BBB. Though various inflammatory cytokines are responsible for TJ protein impairment downregulation of Claudin 5, a major TJ protein responsible for selective permeability of BBB, is the major causative factors for barrier disruption (Wang et al 2017; Nitta et al 2003).Peripheral inflammation also damages the endothelial cell of the BBB by inhibition of P-gp protein, a critical BBB transporter, activity that results in membrane abnormalities, damage the endoplasmic reticulum and mitochondria, ultimately leading to cell apoptosis (Cardoso et al 2012; Bernhart et al 2018). In Parkinson’s Disease vascular inflammatory markers were unusually higher in peripheral circulation (Yu et al 2020). This was reported to be due to the upregulation of Vascular Cell Adhesion Molecule 1 and Intercellular Adhesion Molecule 1, disturbing the barrier.Glial cell activation plays a substantial role in maintaining the integrity of BBB (Haruwaka et al 2019).

The consequence of peripheral inflammation on different neurological diseases varies, subject to the duration of inflammation and nature of disease.In multiple sclerosis (MS), the dysfunction of the BBB is triggered by oxidative stress and neuroinflammation causing TJ protein alterations and cytoskeletal changes. In addition, modulation of Mfsd2a gene, a major transmembrane protein present in the blood vessels, can upset the BBB (Ortiz et al 2014). This was witnessed when ablation of Mfsd2a gene in mice demonstrated a leaky BBB from embryonic stage to adulthood (Ben-Zvi et al 2014). Subsequent to a ruptured BBB, peripheral monocytes permeate into the site and begin to phagocytose myelin causing demyelination.Alzheimer’s disease is mainly associated with amyloid plaque deposition and microglial cells play a key role in amyloid protein processing (APP) and dysregulation of it causes plaque deposition. The resulting Aβ oligomers again activate the microglia and perivascular cells further to generate ROS. The resulting oxidative stress downregulates tight junction proteins and disrupts the BBB (Sweeney et al 2018). Microglial Toll Like Receptor-4 is instrumental in APP and the Lyn Kinase protein in it modulates plaque formation. Absence of Lyn protein in mice increased Aβ phagocytosis and decreased neuronal dystrophy, as observed by Islam et al (2025).

Acute neuroinflammation is an adaptive physiological immune response to protect and preserve the integrity of the central nervous system in response to injuries (Wyss-Coray and Mucke 2002). This healing process is mediated by a complex series of mechanisms at the cellular as well as the molecular level, primarily revolving around microglia and astrocytes (Ransohoff and Brown 2012). Key role of acute neuroinflammation is phagocytic clearance of apoptotic neurons, infection mediators and cell debris to prevent accumulation of neurotoxic elements that can further damage the surrounding nervous tissue (Wang et al 2022). Moreover, acute neuroinflammation often stimulates neurogenesis through growth factor (BDNF) upregulation, to help in the functional recovery of the affected region of the brain (Numakawa et al 2018).

When the neuroinflammatory process gets prolonged due to constant or recurring insults it becomes chronic, and it is instigated by a cascade of deleterious mechanisms mediated by the excessive activation of the same glial cells which were initially protective (Kempuraj et al 2017). Prolonged activation of microglia and astrocytes escalates the expression of proinflammatory cytokines, like TNF α, IL 1β, etc. (Simpson and Oliver 2020). This, in turn, amplifies oxidative stress and inflammation leading to chronic neuroinflammation and associated progression of neurodegenerative disorders (Teleanu et al 2022).

Neuroinflammation is primarily driven by reactive astrocytes and microglia as well as peripheral proinflammatory cells that, after receiving signals, can cross the BBB and enter the CNS (Gullotta et al 2023). The major setback of chronic neuroinflammation is cognitive impairment that might affect the individual’s quality of life. It is a well-known fact that AD, one of the widespread neurodegenerative diseases, is characterized by learning impairment and memory incapability. This cognitive deficit associated with AD is believed to be due to chronic inflammation and AD exhibits a definite pattern of neuropathology like densely packed highly activated microglia and astrocytes along with elevated proinflammatory cytokines (McGeer and McGeer 1998; Akiyama et al 2000).

Microglia are derived from monocyte precursor cells and are known to be the brain-resident macrophages. Microglia mainly act like brain macrophages by removing cell debris, unnecessary synapses, microbes and other redundant substances and stabilize the microenvironment of the central nervous system (Ginhoux et al 2013; Ueno et al 2013; Araujo and Cotman 1992). Also, microglia contribute significantly during neurogenesis by maintaining neuron health and formation of the neuronal circuit. Under normal conditions, the microglia safeguard neuronal survival and provide immunity. They display dynamic adaptation in their shape from a ramified (resting phase) one to an amoeboid like (active phase), depending upon the normal physiological or pathological stimulation (Nimmerjahn et al 2005). Moreover, excessive aggregation of amyloid β leads to over-activation of microglia and consecutively undue release of pro-inflammatory cytokines and now they are referred as DAM—disease-associated microglia (Wolf et al 2017). Studies have proven that the binding of TLR4 and Aβ activates microglia, and the pattern recognition receptors help to detect the Aβ (Jin et al 2008; Tahara et al 2006). In mice model of AD, an increase in inflammatory cytokines production, phagocytosis inhibition and higher plaque accumulation was observed to be mediated through TLR4 signalling. Upon the inception of inflammation due to traumatic brain injury, microglia interact with the astrocyte to induce astrocyte-derived ATP gradient, which regulates the dynamics of microglial processes. Subsequently, these processes rapidly converge at the site of injury and help to establish a barrier between injured and healthy brain tissue (Davalos et al 2005; Haynes et al 2006). Another protective role of microglia is reported by Lou et al., wherein these glial cells facilitate repairing the breached BBB through purinergic receptor-mediated process (Lou et al 2016). However, when there is prolonged injury chronic inflammation sets in and the microglial processes retract due to the downregulation of purinergic receptor-mediated pathway and upregulation of the A (2A) adenosine receptor (Orr et al 2009). Additionally, this injury activated microglia secrete pro-inflammatory cytokines that can induce neurotoxic reactive A1 astrocytes (Liddelow et al 2017). These reactive A1 astrocytes outrun their normal beneficial function and become cytotoxic, which empowers them to destroy neurons & oligodendrocytes. Thus, the activated microglia boost neurodegeneration in several neurodegenerative disorders.

Triggered by brain injuries or infections microglia get activated and polarized into M1 or M2 types through different factors. M2 is neuroprotective, responsible for the release of anti-inflammatory cytokines, transforming growth factor (TGF β1) and promote the healing process (Gao et al 2023; Ronaldson and Davis 2020). Meanwhile, when the injurious state becomes severe microglial cells transform into M1 phase, which is proinflammatory, can lead to neuronal damage through the release of inflammatory cytokines, change tight junctions and modulate P-gp protein at the BBB. Their appearance changes to amoeboid shape with large cell body and a number of processes (Umpierre and Wu, 2021; Young and Morrison, 2018). Unwarranted over-activation of M1 microglia exert deleterious effects in neurodegenerative disorders (Tang and Le, 2016). In summary, M1 and M2 microglia switch between functional phenotypes according to different environmental stimuli.

The most abundant of glial cells that are derived from the neural stem cells are the astrocytes (Kriegstein et al. 2009). These cells are crucial in modulating extracellular balance of ions, fluids, removal of free radicals at the BBB as well as synapse formation and synaptic plasticity. In tripartite synapses, astrocytes are of paramount importance in bidirectional communication between them and neurons, which helps in preserving homeostasis and neuronal survival in addition to inter-neuronal communication (Farhy-Tselnicker and Allen 2018). Rodent study model of AD has exhibited reactive astrocytes around amyloid plaque (Kato et al 1998; Wegiel et al 2001). An elevated expression of glial fibrillary acidic protein (GFAP) and vimentin, both are proteins found in reactive astrocytes, were observed during neuronal cell hypertrophy. On the contrary, studies in the APP/PS1 mouse model of AD showed that the decrease of GFAP and vimentin is directly proportional to the astrocytic reaction and inversely proportional to that of the Aβ plaque load (Kraft et al 2013). It is demonstrated through in vitro and in vivo studies that reactive astrocytes form a glial scar and infiltrate Aβ plaque to decrease the damage of the neurotoxicity as well as reduce Aβ deposits by phagocytosis suggesting that it is neuroprotective (Wyss-Coray et al 2003; Xiao et al 2014). Gomez-Arboledas et al, (2018) claim that pathological changes such as impaired neural circuit, inflammatory responses and Aβ-mediated pathology can be reversed by improving the phagocytic potential of astrocytes. As mentioned earlier the injury activated microglia induce the generation of reactive A1 astrocytes which can further aggravate inflammation (Liddelow et al 2017).

Myelin loss and oligodendrocyte dysfunction are important variables that facilitate the progression of degenerative disorders of the brain (Han et al 2022). This malfunction sets off a series of events that eventually result in axon degeneration and neuronal cell death. These events include increased oxidative stress, mitochondrial failure, and ion channel redistribution along with denuded axons. Viral infections, acute demyelinating encephalomyelitis, and chronic illnesses like MS can cause impaired oligodendrocytes, which are evident in inflammatory disorders of the neurological system (Peferoen et al 2014). Beyond their role in myelination, oligodendrocytes are vital for ensuring axonal integrity, supporting axonal metabolism, and facilitating neuronal survival (Han et al 2022; Peferoen et al 2014; Li and Sheng 2023; Bankston et al 2013; Funfschilling et al 2012;). Oligodendrocytes can produce immune mediators in response to stress, have the ability to alter the microglial activation status, which in turn releases chemo attractants like CXCL10, CCL2, and CCL3 to recruit microglia to damaged tissues (Balabanov et al 2007; Ramesh et al 2012). Additionally, oligodendrocytes express beta-crystallin, a heat-shock protein, that activates microglia and plays a role in the pathophysiology of neurodegenerative illnesses like multiple sclerosis (Peferoen et al 2014; Balabanov et al 2007; Ramesh et al 2012).

Antigen-presenting cells (APC), BBB permiability and lymphatics are primary defence mechanism that makes the brain an immune–privileged organ (Cheng et al 2023; Zhang et al 2019; Chen et al 2021; Parvez et al 2022). These systems collectively maintain CNS homeostasis and protect against peripheral immune system invasions. However, in pathological conditions such as stroke, these defences can be compromised. When the integrity of the BBB is disturbed, peripheral immune cells can infiltrate the affected brain regions. This invasion is exacerbated by the subsequent drainage of these cells through the CSF into the deep cervical lymph nodes, thereby amplifying the immune response (Cheng et al 2023; Cho et al 2022). Notably, peripheral immune cells have been observed within the brain parenchyma during the onset of stroke, highlighting the significant breach in the brain’s protective barriers. In essence, following a deleterious insult or pathology, the destruction of the BBB enables the entry of harmful substances and APCs into the CNS. This breach facilitates the recruitment of peripheral immune cells, which in turn propagates neuroinflammation (Cheng et al 2023). Consequently, the progression of neurodegenerative diseases is significantly influenced by peripheral immune cells.

Multiple factors contribute to neuroinflammation that might result in neurodegeneration (Chang RC, 2009; Lyons A, 2009). Numerous epidemiologic, clinical, and animal model studies conducted over the past decades advocate that in most cases the CNS insult is associated with the glial cell activation, mainly astrocyte and microglia, along with proinflammatory cytokine rise. The neuroinflammatory process involves three major steps: the microglia and the resident macrophages facilitate inborn immune responses (Chausse et al 2021), the peripheral immune cells infiltrate into the CNS (Castellani et al 2023), and such infiltrated T-cells provide adaptive immunity (Korn and Kallie 2017; Gate et al 2020; Congdon et al 2019). Microglial cells are vital in the maintenance of brain homeostasis and support brain development (Chang et al 2009; Lyons et al 2009). However, the astrocytes are mainly responsible for the smooth circulation of blood, and they also supervise the optimum neurotransmitter level to provide an ideal microenvironment for neurological function. In the absence of inflammatory triggers, the anti-inflammatory cytokines, neurotrophic factors, or intercellular contacts supresses overactivation of these glial cells via CD200/300 receptor interactions, neurotransmitters, neurotrophic factors, and anti-inflammatory cytokines.

Role of proinflammatory cytokines (TNF-α & IL-1β & 6) in modulation of synaptic plasticity is well known (Singh et al. 2024a; Heir and Stellwagen 2020). Among these cytokines, TNF-α exerts its effect on synaptic plasticity in a concentration dependent manner. Low or optimal level of TNF-α facilitates synaptic plasticity and substantially increased level of TNF-α as in conditions of neuroinflammation impairs the long-term potentiation (LTP) of excitatory neurotransmission leading to dysregulation of synaptic transmission and plasticity (Maggio and Vlachos 2018). Additionally, increased microglial activation during neuroinflammation adds to the pathological enhancement in TNF-α concentration, since microglia is known as the major source of this cytokine (Shemer et al 2020). TNFα acts on astrocytes to modulate synaptic neurotransmission, providing evidence for a relevant crosstalk between glial cells (Santello et al 2011). Moreover, TNF-α affects neuroplasticity by altering the glutamatergic pathway, wherein it alters the expression of glutamate receptors. It intensifies the internalization of AMPA receptors and interrupts the functioning of NMDA receptors. This causes diminished LTP, which is essential for cellular correlation of learning and memory (Henley et al. 2013). Among other cytokines, the IL-1β hampers LTP by altering BDNF-TrkB (Tyrosine kinase B) signaling that is essential for strengthening the synapses. It also triggers stress related p38 MAPK (Mitogen activated protein kinase) that negatively affects neurogenesis in the dentate gyrus (Tong et al. 2012). Elevated expression of IL-6 during neuroinflammation adversely affects JAK/STAT3 signaling pathway, the vital pathway for regulating neuronal growth and survival (Lee et al 2016). It also decreases the synaptic protein expression, disrupting glutamatergic transmission and thereby dysregulating synaptic plasticity (Gruol 2015).

Identifying the molecular mechanisms of the specific gene might help in minimizing the progression of neurodegenerative disorders significantly. Though there are multiple factors involved in neurodegenerative diseases, the contribution of genetic factors cannot be ignored since Apolipoprotein E (APOE) gene variant-related pathway amplified the risk of late-onset AD (Heneka 2023; Rosenthal and Kamboh, 2014, Yamazaki et al 2016). APOE variants increase the risk of Aβ protein aggregation and tau pathology in both human (Hashimoto et al 2012; Koffie et al 2012) animal model (Youmans et al 2012). Among the variants, the APOE4 & TREM2 can exacerbate neuroinflammation by escalating the release of pro-inflammatory cytokines by activated glial cells. It also impedes amyloid β clearance, which can further accelerate microglial activation, eventually leading to impaired synaptic plasticity and cognitive deficit (Heneka et al., 2023).

These variants are associated with a distinct microglial activation state termed “disease-associated microglia” (DAM), which initially serves a protective role but may become maladaptive with prolonged activation (Keren-Shaul et al. 2017).

The pathological sequence of neurodegeneration is a cycle where mainly amyloid and tau protein aggregates induce neuroinflammation, followed by neurodegeneration and cognitive impairment, which further facilitates protein aggregation worsening the condition. In the aged population other than the increased release of neuroinflammatory cytokines due to various influences, the hormonal imbalance also plays a pivotal role. In women decline in estrogen level increased the risk of AD and associated cognitive impairment, witnessed in both human and animal studies (Li et al 2014; Vegeto et al 2006; Yue et al 2005). Whereas males have a higher risk of Parkinson’s disease, in comparison to females (Wooten et al 2004).

Older adults are usually more prone to neurodegenerative diseases (NDs), since advancing age is the major risk factor for inflammation-induced neurodegeneration. This can be credited to increased pro-inflammatory cytokines, tau and amyloid aggregation, impaired mitochondrial function in response to various types of tissue insults during their life-time (Azam et al. 2021). Similarly, progression of several NDs such as Alzheimer’s, Parkinson’s, MCI, depression or Amyotrophic Lateral Sclerosis exhibits gender differences. Thes can be attributed to hormonal influence or genetic factors like APOE protein variant (Nicoletti et al 2023). Genetic variation in immune-associated signals may contribute to altering the expression and function of immune signals independent of pathogen exposure (Sekar et al 2016).

The sex hormones play a significant role in neurodegenerative diseases like AD, PD etc. (Ardekani et al. 2016). In-Vitro studies have revealed that sex hormones, testosterone and estradiol exert varied effect on the cleavage of tau proteins (Yeap and Flicker 2022). Since estrogen has a neuroprotective property in women, a decline in estrogen level is associated with AD (Villa et al 2016; Wise et al 2001). Therefore, the risk of AD development in perimenopausal women is more than the elderly men (Green and Simpkins 2000). In a transgenic mouse model overexpressing amyloid precursor protein, downregulating aromatase expression increased testosterone and reduced estradiol concentrations, and reduced plaque formation within the brain, inferring a role for testosterone rather than estradiol to protect against Alzheimer’s disease (Yeap and Flicker 2022; McAllister et al 2010). In vivo studies provided further, strong evidence on the capacity of estrogens to inhibit neuroinflammatory processes, by modulating the receptors in microglia (Lei et al 2003).

Whereas males have a higher risk of Parkinson’s disease (PD), in comparison to females (Wooten et al 2004). In PD, the neurons containing α-Syn aggregates in Lewy bodies cause inflammation and neuron degeneration and produce motor as well as cognitive disorders (Yeap and Flicker 2022). Therefore, inhibition of α-Syn aggregation is considered a promising therapeutic strategy for PD and several other synucleinopathies disorders that are leading causes of dementia worldwide (Khan et al 2024).

Testosterone upregulates glial cell line-derived neurotrophic factor (GDNF) in glioma cells and astrocytes essential for microglial proliferation, migration, and invasion. It also contributes to brain tumor growth via GDNF and inflammation. Testosterone is a crucial hormone that regulates the central nervous system diseases such as brain and spinal cancers by activating oncogenes, pro-inflammatory cytokines, and chemokine synthesis that facilitates astrocyte reactivity, cancer cell proliferation, and tumor progression (Kanwore et al 2023).

Recent studies have shown the link between androgen deprivation therapy (ADT) for prostate cancer and Alzheimer’s disease in older people (Sari Motlagh et al 2021; Hwang et al 2015; Nead et al 2016). Modulation of testosterone, as in prostate cancer treatment, can lead to amyloid aggregation and formation of neurofibrillary tangles, by activating neprilysin (NEP) and eventually cause cognitive decline. Neprilysin is the protein responsible for regulating the accumulation of amyloid β oligomers into amyloid plaques (Qian et al 2021). Alterations in basal testosterone expression can disturb the stability of genes that are sensitive to androgen level, contributing to cognitive deficit (Singh et al. 2024b).

The proinflammatory cytokines released by the activated microglial cells in the course of neuroinflammation are capable of altering neurotransmitter production and receptor sensitivity (Salcudean et al. 2025; Wang et al 2022).

Several studies have shown the connection between neuroinflammation and neuropsychiatric disorders like Major Depressive Disorder (MDD) & Parkinson’s disease which is associated with cognitive disturbance (Robson et al 2017; Remus and Dantzer, 2016). Neurotransmitter serotonin is often associated with mood regulation and is associated with depressive disorder. However, there is no direct link between serotonin depletion and depression (Moncrieff et al 2023). On the other hand, tryptophan (the precursor of serotonin) metabolite kynurenine produced by the enzyme indoleamine 2,3 dioxygenase (IDO) is secondarily involved in cognitive disorder (Wu et al 2019). The Kynurenine mediated pathway other than disturbing serotonergic systems, also leads to deposition of neurotoxic metabolitess such as quinolinic acid, which is known to augment NMDA receptor mediated excitotoxicity (Muneer 2020). IDO is secreted by the microglia, induced by the cytokine interferon-γ. Interestingly, IDO expression was observed to be higher in the hippocampus of mice model of AD and AD patients, along with neurofibrillary tangle and amyloid plaques (Wu et al 2013; Willette et al 2021). Reduction of tryptophan by increased expression of IDO during neuroinflammation might lead to serotonin depletion leading to mood dysregulation (Remus and Dantzer 2016).

Another neurotransmitter dopamine regulates neuroinflammation, influencing microglial activation and supressing activation of NLRP3 inflammasome (Iliopoulou et al 2021; Yan et al 2015), through various dopamine receptors (DR1-DR5) expressed in the immune system. Among these receptors, DR1 and 2 take part in anti-inflammatory mechanism, reducing neuroinflammation (Montoya et al 2019; Wang et al 2018).Whereas DR3 and DR5-associated signaling pathway facilitate neuroinflammation (Contreras et al 2016; Osorio-Barrios et al 2018). In this regard, it has been shown that human microglia express DRD1-DRD4 (Masteroeni et al. 2009), whilst DRD1, DRD2, DRD4 and DRD5 have been found in rat microglia (Farber et al 2005).

The influence of neurotransmitter glutamate associated pathway is crucial for maintaining the integrity of neuronal cell membrane and there by facilitating appropriate neurological function.

(Sears and Hewett 2021). Inhibitory signals in the path neuronal transmission are mediated by GABA, while excitatory signals are mediated by glutamate, any imbalance in this circuit is known to cause excitotoxic injury in hippocampus, the memory-associated region (Zhou et al. 2021; Takeuchi 2010). Activated microglia during chronic neuroinflammation modulates glutamate synthesis and disruption of the balance between glutamate and GABA has a functional role in various pathologies, including traumatic brain injury, Alzheimer’s disease, epilepsy, schizophrenia, and depression (Sears and Hewett 2021; Wong et al 2003).

Neuroinflammation in response to injury or infections in the brain, initially acute to repair the injured tissue can lead to chronic stage when sustained for a long period. It is regulated by both positive and negative feedback mechanisms or loops. Negative mechanism encourages resolution and reduces inflammation (Bhol et al 2024), while positive mechanism aggravates the inflammation (Glass et al 2010, Ofengeim et al. 2017). Understanding both the mechanisms are necessary for developing therapeutic approaches.

Positive feedback loop involves cytokine storms wherein initially protective pro-inflammatory cytokines trigger over-production of themself when inflammation gets sustained for a prolonged period. Simultaneously, activated microglial cells further enhance the generation of proinflammatory cytokines (Glass et al 2010) and reduces amyloid beta protein clearance through kinase RIPK1 upregulation, leading to plaque formation and apoptosis of neurons that was observed in mice model of AD (Ofengeim et al. 2017).

Negative feedback loop involves anti-inflammatory cytokines, neurotrophins like BDNF and transcription factors like NF-κB performaning crucial roles in the resolution of inflammation. Excessive activity of proinflammatory cytokines can be dampened by the counter activity of anti-inflammatory cytokines (Bhol et al 2024). Neurotrophic factor BDNF aids in resolving neuroinflammation by regulating the crosstalk between microglia and astrocytes. It promotes neuronal survival and encourages microglia to supervise the cyclooxygenase-2 expression and transcription factor NF-κB (Giacobbo et al 2019; Lai et al 2018; Liu et al 2017). Understanding the mechanism of both negative and positive feedback loops is advantageous while developing novel therapeutic strategies for the alleviation of neuroinflammation.

Mitochondria are the major source of energy supplier for neuronal survival. Therefore, impaired mitochondrial function and resulting oxidative stress play a critical role in intensifying the process of neuroinflammation. It is reported that neuroinflammation in major neurodegenerative disorders like AD, PD or ALS are linked to impairment in mitochondrial function (Qin et al 2024; Peggion et al 2024). In AD, excessive oxidative stress impairs mitochondrial function and this vulnerability of mitochondria to oxidative stress is attributed to the lack of histones (Tan et al 2018). Removal of these impaired mitochondria by the autophagic (mitophagy) process also gets affected. Declined ATP generation contributes to the accumulation of amyloid-beta (Aβ) fibrils and hyperphosphorylated tau protein tangles, which lead to synaptic dysfunctions and cognitive impairments (Rai et al 2020; Bergamini et al 2004). In human AD brain also amyloid β accumulation was associated with mitochondrial dysfunction, as reported by Devi et al. (2006). This suggests that loss of ATP production and subsequent enhancement in ROS generation plays a pivotal role in the progression of neurodegenerative disease. The voltage-dependent anion channel proteins (VDAC) are responsible for metabolite diffusion between the mitochondria and cytosol (Hodge and Colombini 1997). Aggregated Aβ interacts with VDAC1 and blocks the mitochondrial permeability transition pore (MTP) that obstructs the diffusion of mitochondrial proteins from the nucleus. This leads to oxidative phosphorylation, enhancing free radical generation (Manczak et al 2011; Manczak and Reddy 2012). Damaged mitochondria generate damage-associated molecular patterns (DAMP) or alarmins like mtDNA, cytochrome C and cardiolipin, which can activate microglia and astrocytes and enhance production of proinflammatory cytokines by these glial cells further compromise functioning of mitochondria and escalate neuroinflammation (West et al 2011; Glass et al 2010).

Aggregated Aβ and hyperphosphorylated tau proteins interact bidirectionally, to initiate neuroinflammation as well as they get accumulated along the course of the inflammatory process, further amplifying neuroinflammation. Accumulated Aβ proteins bind to the recognized receptors (TLRs) and NOD-like receptor protein 3 inflammasomes, on microglia and trigger the immune reaction by releasing the proinflammatory mediators (Islam et al 2025; Heneka et al 2015). Aggregated form of hyperphosphorylated tau proteins trigger NF-κB signaling in microglia, promoting the release of pro-inflammatory cytokines that further escalate tau pathology (Maphis et al 2015). It is suggested that the interleukin 1β that is released from activated microglia drives tau pathology. Additionally, chronic neuroinflammation augments hyperphosphorylation of tau by upregulation of GSK-3β as well as CDK5 kinases and it also hampers microglial phagocytosis and autophagy-lysosomal pathway for clearance of tau (Pascoal et al 2021; Kinney et al 2018).

Recurring gut infections and cognitive impairment have long been linked to systemic inflammation (Perry et al 2003, 2007). Recent studies have revealed that peripheral insults associated with systemic inflammation when sustained for a prolonged period can lead to neuroinflammation (Perry et al 2003; Amor et al. 2014; Wendeln et al 2018; Dinan and Cryan 2017). Currently, emerging evidence implicates gut microbiota dysbiosis with several neurodegenerative disorders (Fang et al 2020). Bidirectional connection between the gut and brain, the gut-brain-axis takes place through the immune cells, vagus nerve and microbial metabolites (Collins et al 2012; Doifode et al 2020). Other than its metabolic and protective functions, gut microorganisms have a crucial role in maintaining immune homeostasis (Guarner and Malagelada 2003). A number of neuropsychiatric disorders have displayed abnormalities in the composition of gut microorganisms like autism spectrum disorder (Lim et al 2017), depression (Naseribafrouei et al 2014), AD (Cattaneo et al 2017), Parkinson’s disease (Perez-Pardo et al 2017). Therefore, modulating peripheral immune response, particularly aiming at the gut microbiota, appears to be a beneficial therapeutic approach in alleviating neuroinflammation and associated cognitive deficit (Akbari et al. 2016). These therapeutic modulators can be incorporated in the form of dietary fibres, prebiotics or probiotics, which aid in the growth of beneficial bacteria. Additionally, peripheral immune responses can be improved by short-chain fatty acids (SCFAs) metabolites, which are produced by the gut microrganisms, mainly through fermentation of dietary fibres (Silva et al 2020). They improve the T-cell responses, which help in suppressing excessive immune responses. They also promote maintenance of microglial homeostasis and thus provide an environment for reducing inflammatory response in the brain. In this way, peripheral inflammation can be modulated, and this might help indirectly in mitigating neuroinflammation and associated cognitive decline. Therefore, supplementation of SCFA either directly or indirectly through diet appears to be a promising treatment for neurodegenerative diseases.

There are numerous studies on different animal models of neurodegenerative diseases, to explore the neuroinflammatory mechanisms that transform acute into chronic neuroinflammation. But these models come with certain limitations, because different animal models exhibit varied pathological appearances of neurodegeneration like deposition of amyloid plaques, tau aggregation, lewy bodies or glial activation (Banik et al 2015). Major limitation is the variability in the genetic constituents of animals and humans, though the discovery of new knock-in mouse models closely mimic physiological models of AD (Drummond and Wisniewsk 2017). Though studies in non-human primates are better options because of their greater similarity in genetic combination of humans and resemblance to physiological development of AD (Rai et al. 2024, Heuer et al 2012; Jucker 2010; Teschendorf and Link 2009), there are limited studies on these models because of availability, cost and inconsistency in the extent of pathology in all animals. Hence, it is necessary to conduct preclinical testing in various animal models that closely imitate neuroinflammatory process and the complexity of the mechanism for assessing long-lasting and affordable therapeutic strategies.

Aging and neuroinflammation: Aging in the healthy brain is characterized by a low-grade, chronic, and sterile inflammatory process known as neuroinflammaging (Soraci et al 2024). As age advances, reactivity of the neuroimmune environment increases owing to the elevated level of proinflammatory cytokines in response to various environmental or genetic factors. Neuroinflammaging weakens neurogenesis (Spalding et al 2013), compromises mitochondrial function (Grimm and Eckert 2017) and neuroplasticity, especially in the hippocampal areas, and in turn accelerates cognitive deterioration. Moreover, aged microglia are no longer capable of establishing effective immune responses and sustaining normal synaptic activity, directly contributing to age-associated cognitive decline and neurodegeneration (Costa et al 2021).

Metabolic conditions and neuroinflammation: Whereas, in metabolic conditions like diabetes and obesity systemic inflammation induces neuroinflammation, driven by adipose-derived cytokine such as leptin & IL1β, which can trigger BBB disruption and enable peripheral immune cell infiltration in the brain (De Felice and Ferreira 2014). Moreover, in diabetes, impaired insulin signaling alters PI3K/Akt and MAPK pathway, adversely affects neurogenesis, enhances oxidative stress and neuronal cell apoptosis (Arnold et al. 2018). Obesity is associated with chronic but low- grade peripheral inflammation (Zattarale et al. 2020). In obese patients, fat metabolism gets disturbed leading to augmented free fatty acid level in circulation. These fatty acids bind to pattern recognition receptors on immune cells and enhance the release of proinflammatory cytokines in the circulation triggering systemic inflammation-driven neuroinflammation (Litwiniuk et al 2021). Moreover, they also adversely affect mitochondrial function, thereby producing free radicals that increase oxidative stress (Hoeks and Schrauwen, 2012).

Glial-dependent lymphatic transport, the glymphatic system eliminates waste products like metabolites, inflammatory cytokines, chemokines & soluble proteins from the brain. This function is facilitated by aquaporin-4(AQP4) water channels on astrocyte end feet, empowering exchange between CSF and interstitial fluid (Iliff et al. 2013). The glymphatic system regularly filters neurotoxic substances from the brain, primarily during sleep and in wide-awake state it is disconnected (Reddy et al. 2020; Jessen et al 2015). Sleep induces a decline in the level of noradrenaline, leading to expansion of the extracellular space, which facilitates smooth flow and filtration of the CSF, improving the waste clearance (Plog and Nedergaard 2018). Effectively functioning glymphatic system helps to maintain the microenvironment of the nervous tissue by clearing the waste and preventing build-up of neurotoxins. Weakened glymphatic system, due to various brain insults like traumatic brain injury, infections or aging can lead to reduced clearance and subsequent accumulation of inflammatory mediators (Rasmussen et al. 2018). Such dysfunctional glymphatic system is linked to the pathogenesis of neurodegenerative diseases, like AD (Reddy et al. 2020), which has the characteristic feature of amyloid β and tau protein accumulation. Consequently, dysfunctional glymphatic system intensifies neuroinflammatory process, leading to neurodegeneration induced by chronic inflammation (Plog and Nedergaard 2018). Therefore, neurotherapeutics focused on the improvement of glymphatic clearance system might help in curbing the progression of neurodegeneration (Reddy et al. 2020).

Though there are multiple factors that contribute to the growth of the body, it can also be affected by inflammation in early or prepubertal periods of life. Proinflammatory cytokines like TNF α plays a role in growth of the bones or tissue cell proliferation and it acts by interfering with the release of IGF 1 (Insulin like Growth Factor 1), the function of which is to manage the effects of growth hormones in the body (Zhao et al 2014; Choukair et al 2014). Due to an imbalance in the activities of these components growth of the child can be affected in an early age, leading to short stature (SS). Zinc plays a significant role in regulating inflammation through various mechanisms. It exhibits anti-inflammatory properties by effectively preventing the activation of NF-kB, a transcription factor involved in the expression of numerous proinflammatory genes (Garcia et al. 2013). Pro- inflammatory markers TNF-α and IL-6 were raised significantly in the SS group of the study (Yadav et al 2024). According to them Cu/Zn ratio along with TNF α and IL-6 can be utilized as one of the markers to investigate short stature in early years of life before puberty and they advocate Zn supplement could help in the growth of the bone by modulating TNF α and IL-6 level in chondrocytes of the developing bone.

Knowing the fact that neuroinflammation is a multifaceted biological response, triggered by several factors like enhanced inflammatory cytokines, activated glial cells, gut microbiota or genetic predisposition, the development of a specific treatment approach remains a challenging procedure. Most of the therapeutic strategies for neuroinflammation-induced neurological diseases include cytokine inhibitors, microglial modulators and antioxidants. Despite the intricacy of the neuroinflammatory process and the complexity of signaling pathways of neuroimmune response, several therapeutic strategies are showing promising results (García-Dominguez 2025). These include NLRP3 inhibitors (e.g., MCC950), tetracycline derivatives (e.g. minocycline), glucocorticoids, and biologics targeting key cytokines such as IL-1β (e.g. anakinra) and TNF-α (e.g. etanercet) (Naeem et al 2024; Jiang et al. 2012; Komoltsev and Gulyaeva 2022; Mallick et al 2025) or specialized pro-resolving mediators (SPMs) like resolvins, protectins, etc. (Ponce et al 2022; Valente et al 2022; Li et al 2020). Another pathway that promotes neurogenesis, helps in maintaining BBB and thus neuroprotective is Wnt/-catenin (WβC) signaling pathway and irregularities in this pathway is associated with several well-known neurodegenerative disorders (Ramakrishna et al 2023).

Chronic neuroinflammation has been linked to the progression of neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as conditions like depression and schizophrenia. Understanding the neuroinflammatory responses in specific cognitive regions of the brain and the role of immune cells might provide critical insights into the mechanisms underlying cognitive impairment and neurodegeneration associated with neuroinflammation.

Though there are a significant number of treatment options for neuroinflammation and related neurodegenerative diseases, majority of them are symptomatic, because of the complexity of the mechanisms involved in the neuroinflammatory process (Gadhave et al 2024). Understanding the precise mechanism is the major challenge in the development of neuro-therapies that can effectively mitigate neuroinflammation with minimal adverse effects. In-depth knowledge about the energetic role of glial cells and peripheral immune cells in different neurological and neuropsychiatric disorders is the need of the hour in the course of discovery of the neurotherapeutics (Ransohoff 2016). Though there a number of biomarkers and novel neuroimaging techniques to monitor the progression neuroinflammatory process, still there are significant challenges that need to be addressed. Multifaceted approaches like improvement in the delivery of drugs across the BBB, disease specific cytokine centred treatment and improving the gut microbial environment with lifestyle changes would help in inhibiting the progression of neuroinflammation and associated cognitive dysfunction in various neurodegenerative diseases.This review is an attempt to summarize the reports implicating neuroinflammation in specific brain regions with cognitive deficits which would help in developing novel therapeutic strategies aiming at the modulation of neuroinflammation and improving cognitive functions.