Exploring non-canonical targets in Alzheimer’s disease: a departure from the norm

AD is distinguished by a primary deficit in episodic memory. The presence of this ailment frequently coincides with a variety of intellectual deficits in domains such as organizational skills, speech, visuospatial abilities, and decision-making. Therefore, AD manifests as a gradual decline in cognitive abilities, particularly impairing the individual's capacity for making decisions [25]. On average, individuals diagnosed with AD have a survival period ranging from 7 to 10 years. Furthermore, it is important to note that there is presently no definitive diagnosis for this particular illness prior to death. The existence of senile plaques (SP), neurofibrillary tangles, and synaptic loss can only be confirmed via histological examination after death. This poses significant challenges in terms of early detection and intervention [14, 26].

SP is a well-established neuropathological characteristic seen in brains afflicted by AD and continues to be a plausible source of synaptic and neuronal degeneration. SP arises from a gradual buildup of Aβ inside the parenchyma [27].

The intricate process of Aβ formation from the APP via β- and γ-secretase complexes holds crucial significance in AD. The amyloidogenic pathway’s heightened activity in AD, potentially influenced by genetic irregularities in APP or β-secretase, underscores their role in initiating this pathological cascade [28]. Despite linking most AD cases to mutations in APP and β-secretase, the root causes of dementia largely remain elusive. [29]. This mystery is compounded by the fact that 96% of dementia cases are sporadic, lacking identifiable genetic alterations. Individuals affected by these cases exhibit Aβ accumulation without clear underlying changes, highlighting the complexity of dementia’s etiology and necessitating deeper exploration beyond identified genetic factors [30].

Hence, it has been postulated that changes in the breakdown or clearance of Aβ may also have a pivotal influence on the etiology of AD. The detrimental impacts of Aβ, as shown in both human subjects and experimental animals, include a spectrum of effects ranging from freely dispersed oligomers to densely aggregated SP [31, 32]. Various forms of Aβ have been linked to synaptic deterioration and the emergence of neuritic dystrophies. Moreover, some studies have posited that the aggregation of Aβ, similar to SP, could possibly play a role in the decline of dendritic spines [32]. Furthermore, it has been shown that senile compact plaques are linked to the atypical curvature of adjacent neurites and have the potential to disrupt cortical synaptic integration. There has been a suggestion that the presence of Aβ alone may have the ability to induce neuronal cell death in the hippocampus and entorhinal cortex during the progression of AD. Furthermore, these regions have significant relevance in the processes of learning and memory, rendering them very susceptible to the impact of this ailment.

Aβ deposition is seen in the cerebral amyloid angiopathy (CAA) context, which is prevalent among the majority of individuals with AD [33, 34]. This deposition leads to the degradation or disruption of the BBB, hence impacting its overall performance. However, CAA may also manifest independently of AD, hence potentially serving as an indicator of vascular dementia (VaD) [34].

The deposition of Aβ pathology occurs prior to the occurrence of another significant neuropathological characteristic of AD, which involves the hyperphosphorylation and aggregation of tau protein into neurofibrillary tangles. Tau is a protein that is closely connected with microtubules and is highly expressed in the brain. It interacts with tubulin, facilitating the formation of microtubules. It provides support to various cytoskeletal structures and has a regulatory role in several key activities inside neurons. The involvement of tau protein in the pathophysiology of AD is significant, since its aberrant phosphorylation leads to its accumulation as intraneuronal deposits. These deposits manifest as filamentous aggregates in the soma and proximal dendrites [35].

Myelin, a multilayered membrane formed by specialized glial cells called mature oligodendrocytes, wraps around the axons of most neurons in the central nervous system (CNS). This essential structure is pivotal for the proper functioning of neural circuits, enhancing the transmission of nerve impulses through a process known as saltatory conduction. The efficient transmission of signals along myelinated axons is crucial for cognitive processes, motor functions, and overall neural communication. Oligodendrocytes originate from precursor cells known as oligodendrocyte progenitor cells (OPCs) [36]. The transition from OPCs to mature oligodendrocytes involves several stages: proliferation, migration, and differentiation. This intricate process results in the insulation of neuronal axons, allowing for rapid and efficient signal transmission [37]. In the context of neurodegenerative diseases, particularly AD, the remodeling and integrity of myelin become increasingly critical. AD is characterized by the accumulation of amyloid plaques and neurofibrillary tangles, which disrupt normal neuronal function and communication. Changes in myelin and oligodendrocyte function have been shown to play a significant role in the pathophysiology of AD. Studies suggest that alterations in myelin may contribute to the clinical manifestations and cognitive decline associated with the disease [38]. The myelin sheath is primarily composed of lipids, accounting for about 40% of CNS lipids. The lipid composition includes approximately 50% phospholipids, 40% glycolipids, and 10% cholesterol and cholesterol esters, along with polyunsaturated long-chain fatty acids [39]. Cholesterol, which is synthesized mainly by oligodendrocytes from ketone bodies, is critical for maintaining the structural integrity of myelin. It modulates the fluidity and permeability of the axonal membrane, thus influencing the rate of myelination and the overall health of the CNS. Notably, the predominant lipids in myelin—such as galactosyl ceramides and sulfatides—are essential for its stabilization and organization [39]. Research on the structural characteristics of the myelin sheath in AD has utilized advanced imaging techniques, including electron microscopy and magnetic resonance imaging (MRI), in both animal models and human subjects. For instance, the 5XFAD mouse transgenic model, which harbors multiple mutations in the APP and presenilin 1 (PS1) genes, exhibits amyloid deposits and synaptic deficits as early as 1.5 months of age [40]. Furthermore, myelin abnormalities in this model can be detected even earlier, coinciding with the onset of spatial memory deficits around 1 month of age [41]. In humans, studies have revealed a significant correlation between myelin abnormalities and the clinical manifestations of AD. Neuroimaging has shown that myelination irregularities occur in critical brain regions, particularly the hippocampus and corpus callosum—areas integral to memory and cognitive function [42‐44]. The presence of conformational anomalies and thinning of the myelin sheath often precede the appearance of axonal lesions, suggesting a possible link to demyelination. During the preclinical phase of AD, MRI studies reveal changes in both longitudinal and transverse relaxation times, alongside increased myelin hydration levels [45]. Irregularities in white matter structure are frequently observed across various forms of AD, potentially indicating a progressive disease process [46]. Differences in T1-weighted/T2-weighted ratios have been documented between patients at risk and healthy controls, suggesting that early changes in myelin may reflect underlying pathological processes [47]. Several studies have linked myelin structural abnormalities to autoimmune disorders and the concentrations of Aβ1-₄₂ peptides in affected individuals [48, 49]. The evaluation of cortical layer arrangements provides insights into the extent of deterioration, complementing volumetric atrophy data [42, 50]. MRI scans have revealed increased density areas in white matter corresponding to abnormalities associated with amyloid peptides and tau proteins in cerebrospinal fluid (CSF). These changes at the histological level suggest alterations in myelin structure, potentially influenced by factors such as iron ion accumulation [51]. Furthermore, diminished vascularization and oxygen delivery in hyper-dense regions are associated with axonal lesions, inflammatory responses, and disrupted blood–brain barrier permeability, culminating in micro-hemorrhagic structures [52]. Given the crucial role of oligodendrocytes and myelin in maintaining healthy neural communication, therapeutic strategies aimed at enhancing the function of OPCs may hold promise for addressing myelin deficits in AD. Recent studies indicate that antimuscarinic drugs, such as clemastine fumarate and benzatropine, can promote the differentiation of OPCs into mature oligodendrocytes capable of myelination. This effect has been observed both in vitro and in vivo, mediated through interactions with cholinergic receptors on OPCs [53, 54]. Additionally, the Piezo 1 receptor, involved in mechanosensory signaling, may also play a role in OPC behavior. Pharmacological inhibition of this receptor could create a niche environment conducive to OPC rejuvenation, potentially enhancing myelination in vivo [55]. Beyond receptor modulation, the mTOR signaling pathway has been recognized as a critical regulator of OPC development. The small molecule LY294002 has shown promise as a transcriptional regulator within this pathway, rejuvenating aged OPCs by promoting a more receptive state [56].

The synthesis, wrapping, and maintenance of myelin require substantial energy and nutrient supplies [57]. Thus, oligodendrocytes have distinct nutritional prerequisites to sustain their myelination capabilities. Nutrient-based interventions for myelination aim to provide direct substrates for myelin sheath construction and maintain energy supply, ensuring optimal metabolic conditions for oligodendrocytes. Adequate provision of macro and micronutrients is essential for the manufacture and maintenance of myelin, enabling oligodendrocytes to build complex and extensive membrane structures [58]. Specialized dietary formulations and individual nutrients have demonstrated positive effects on white matter health following damage or demyelination. One notable nutritional supplement, Fortasyn® Connect, contains key nutrients such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), uridine monophosphate, choline, phospholipids, and several vitamins (B6, B12, C, E), folic acid, and selenium [59]. Developed to support synapse development in AD patients, Fortasyn® Connect has been shown to exert protective effects on cognitive performance in individuals with mild AD [60, 61]. Moreover, it has demonstrated neuroprotective properties in AD models, likely related to enhanced phospholipid metabolism and the preservation of oligodendrocyte populations following white matter damage [62, 63]. Given the potential for certain nutrients to support white matter maintenance, research into other beneficial compounds is warranted. Nutrients such as sphingomyelin [64], vitamins K and D [65], and taurine [66] have shown promise in protecting white matter from injury or demyelination. While the benefits of nutritional support in healthy aging remain speculative, there is substantial evidence indicating that dietary interventions can positively influence white matter repair and cognitive function in contexts related to white matter pathology. The role of white matter in facilitating communication between different brain regions cannot be overstated. It coordinates a range of activities, including neuronal signaling, cognitive processes, proprioception, motion coordination, and sensory transmission. Despite the limited research on oligodendrocyte function concerning brain aging, significant advancements have been made in identifying both internal and external factors influencing oligodendrocyte activity in aging brains. White matter degeneration throughout the aging process is widely recognized as a significant contributor to cognitive decline and reduced independence in later life. Future research can enhance our understanding of white matter ageing, which may lead to strategies aimed at preserving its functions by leveraging the adaptable properties of the oligodendrocyte lineage. Investigating the various factors contributing to the diminished regenerative capacity of white matter in ageing is ongoing. However, the CNS retains substantial capabilities for myelin regeneration. This assertion is supported by studies of individuals with AD, which indicate that significant myelin regeneration can occur even in advanced disease stages.

Overall, targeted treatments to promote myelin preservation in the ageing population may be crucial for maintaining white matter functions vital for optimal cognitive performance. Given the interplay between oligodendrocyte health, myelin integrity, and cognitive function in AD, further exploration into therapeutic strategies that enhance oligodendrocyte activity and myelin repair could provide valuable insights into managing this complex disease (Fig. 2).

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AD is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and alterations in behavior. One of the hallmark features of AD is the accumulation of Aβ plaques, which are linked to neuroinflammation and neurovascular dysfunction. Recent research has illuminated the critical role of the blood–brain barrier (BBB) in AD pathology, revealing that 80–85% of Aβ types are normally eliminated by the BBB [67]. However, emerging evidence suggests that disruptions in the BBB may serve as early indicators of neurodegenerative conditions, including AD as shown in Fig. 3 [68, 69]. Neuroimaging techniques, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), have greatly advanced our understanding of the BBB's role in AD. These technologies allow for the observation of functional and molecular alterations in the brain associated with AD progression [70, 71]. Animal models of AD, alongside post-mortem human studies, have further highlighted significant changes that occur throughout various brain regions during the disease process [72‐74]. The development of advanced brain imaging methods has significantly enhanced our capacity to detect alterations in blood vessels and the corresponding changes in cerebral blood flow. For instance, Kisler and colleagues (2017) demonstrated how sophisticated imaging can track these vascular changes, providing vital insights into the mechanisms by which cerebrovascular dysfunction contributes to neurodegeneration [23]. Additionally, molecular ligands, such as Aβ and tau, along with glucose and P-glycoprotein analogues like 18F-fluorodeoxyglucose and 11C-verapamil, facilitate in vivo monitoring of BBB transporters and receptor proteins [70]. These advancements have led to a deeper understanding of how dysfunction in cerebral blood vessels relates to neurodegenerative disorders. Recent studies employing dynamic contrast-enhanced MRI have confirmed the collapse of the BBB, revealing heightened gadolinium leakage in individuals with early AD, particularly in both white and grey matter [22]. This breach of the BBB has been substantiated by quantifying the accumulation of neurotoxic proteins derived from the bloodstream, including fibrinogen, thrombin, albumin, and immunoglobulin G (IgG). These proteins have been found to co-localize with Aβ deposits in the cerebral cortex and hippocampus of post-mortem brain tissues [75]. Furthermore, the presence of peripheral immune cells, such as macrophages [76] and neutrophils [77], indicates that BBB disruption allows for increased migration of immune cells from the periphery into the brain, amplifying neuroinflammatory responses. The disruption of the BBB in AD is further compounded by various molecular alterations linked to impaired vascular function. Apolipoprotein E (ApoE) has emerged as a prominent genetic risk factor for AD, with the presence of the APOE ε4 allele associated with numerous detrimental effects, including BBB disruption, reduced cerebral blood flow, neuronal death, and impaired cognitive function, irrespective of Aβ presence [22, 73]. Research has indicated that activation of the cyclophilin A-matrix metalloproteinase 9 (CypA-MMP-9) pathways in pericytes of APOE ε4 knock-in mice leads to the degradation of tight junction proteins, such as ZO-1 and occludin, mediated by matrix metalloproteinase 9 [22, 78]. Moreover, the glucose transporter 1 (GLUT1), which is crucial for glucose transport across the BBB, exhibits significantly decreased levels in brain capillaries affected by AD [79]. Alterations in glucose metabolism are observed to precede neuronal impairment in both human subjects and transgenic models of AD [70, 72]. PET imaging has been employed to quantify concentrations of radio-labelled glucose analogues, revealing significant metabolic dysfunction associated with AD. Emerging therapeutic strategies are exploring the potential of glucagon-like peptide-1 (GLP-1) analogues, such as liraglutide, to address cognitive decline in AD. Research has shown that liraglutide can successfully delay memory decline in mouse models of AD [80] and may have protective effects in humans with obesity and type 2 diabetes [81]. Recent findings indicate that GLP-1 receptor agonists may help prevent the decline of glucose transport across the BBB in patients with AD [82]. While the exact mechanisms remain unclear, it is hypothesized that these agents may enhance GLUT1 levels at the BBB [83]. Data from controlled studies have suggested that individuals with type 2 diabetes receiving GLP-1 receptor agonist therapy experience a decreased incidence of dementia [82]. Furthermore, a phase IIb clinical study demonstrated positive effects of liraglutide on cognitive performance and MRI volume in individuals with mild-to-severe AD [84]. A phase III randomized controlled study is currently underway to assess the efficacy of semaglutide in individuals with early AD (NCT04777396, Novo Nordisk A/S). Historically, the central nervous system (CNS) was considered an immunologically privileged site due to the protective nature of the BBB. However, this view has evolved, and the immune system is now recognized as a key player in the pathogenesis of AD [85]. Microglia, the resident immune cells in the CNS, are central to the neuroinflammatory response associated with AD. They actively monitor the brain environment and become activated in response to cellular damage or pathogen invasion. In the context of AD, microglial activation occurs near Aβ deposits, initiating an innate immune response characterized by the release of pro-inflammatory cytokines and chemotactic proteins that can influence peripheral immune cell dynamics. Despite the well-documented role of microglia in AD, the precise mechanisms governing their interactions with other cellular components and their contributions to disease pathology remain poorly understood. Some immune cells exert their effects locally within the brain, while others may act from distant sites [86]. Uncontrolled neuroinflammation, triggered by microglial activity in response to Aβ, can further compromise BBB integrity [87]. The interplay between vascular dysfunction and neuroinflammation is particularly relevant in AD. Pro-inflammatory cytokines and oxidative stress, associated with Aβ accumulation, exacerbate vascular dysfunction. The presence of Aβ and its lipid carrier ApoE, both encoded by genes linked to AD susceptibility, contributes to a vicious cycle that hinders Aβ clearance by microglial and astrocytic cells, leading to endothelial cell degeneration [88]. The activation of pericytes and vascular smooth muscle cells by Aβ peptides has been shown to worsen BBB integrity through the induction of vasoactivity [89]. In AD mouse models, reactive oxygen species trigger the release of endothelin-1, leading to pericyte contraction and subsequent capillary constriction, which ultimately reduces cerebral blood flow. Evidence of vascular inflammation in AD patients is accumulating, with studies reporting elevated levels of adhesion molecules associated with endothelial activation, including vascular cell adhesion protein-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin in plasma samples [90, 91]. Recent investigations have advanced our understanding of how vascular inflammation impacts BBB permeability, highlighting the role of complement components in modulating inflammatory responses in both elderly and transgenic mice [92]. The tau protein is another critical player in AD pathophysiology and BBB integrity. Under normal conditions, tau functions to stabilize microtubules, essential for intracellular transport in CNS cells. In tauopathies like AD, tau undergoes post-translational modifications such as hyperphosphorylation and truncation, leading to its aggregation into neurofibrillary tangles. This aggregation not only disrupts neuronal function, but also activates glial cells, prompting an inflammatory response that alters BBB structure and function. This inflammatory cascade can enhance tau hyperphosphorylation and promote neurofibrillary tangles' formation, creating a detrimental feedback loop [93]. In conclusion, the intricate relationship between the BBB, neuroinflammation, and metabolic dysfunction underscores the multifaceted nature of AD pathology. Disruptions in the BBB facilitate neuroinflammatory processes and neuronal damage, while metabolic alterations, such as impaired glucose transport, further exacerbate cognitive decline. Ongoing research into therapeutic strategies targeting these pathways, such as GLP-1 receptor agonists, holds promise for modifying disease progression and improving outcomes for individuals affected by AD.

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AD is characterized by a complex interplay of pathologic features, primarily the accumulation of extracellular Aβ plaques and the formation of intracellular neurofibrillary tau tangles. Despite extensive research and the development of therapies targeting these hallmark pathologies, clinical trials have often yielded disappointing results, indicating that additional cofactors may significantly influence disease progression [95, 96]. Recent studies have increasingly focused on the relationship between inflammatory processes, immunometabolism, and the amyloid and tau pathologies observed in AD models [97, 98]. There is a growing consensus that metabolic disruptions are crucial in mediating microglial-induced neuroinflammation. For instance, Devanney and colleagues (2020) reported that such metabolic dysfunction could significantly contribute to the neuroinflammatory processes underlying AD [99].

One notable aspect of this metabolic disruption is the age-related decline in glucose metabolism in the brain, termed hypometabolism. This decline has been associated with cognitive impairments in individuals with mild cognitive impairment and AD as shown in Fig. 4 [100, 101]. Furthermore, studies by Schilling and colleagues (2019) indicated that hypometabolism correlates with Aβ deposition and white matter disruption, which can exacerbate cognitive decline [102]. There exists a significant relationship between glucose hypometabolism in AD brains and dysregulation of mitochondrial calcium in neurons, potentially leading to neuronal death [103]. Moreover, the presence of Aβ peptides in mitochondria has been suggested as a factor contributing to neuronal death [104]. Interestingly, limited evidence points to hypometabolism being associated with altered homeostasis of glucose transporters. Specifically, GLUT1 and GLUT3 levels are diminished in the cerebral cortex, while GLUT2 levels increase, presumably as a compensatory mechanism for reduced ATP production [105].

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Experimental models of AD have revealed the roles of astrocytes and microglia in disrupting metabolic processes. Exogenous Aβ has been shown to reduce GLUT1 levels, thereby impairing glycolytic capacity in cultured astrocytes derived from transgenic AD mice. This impairment hampers both glucose uptake and lactate production [106]. Additionally, calcium dysregulation within astrocytes can activate pro-inflammatory regulators through NF-κB and HIF-1 pathways, leading to increased production of reactive oxygen species (ROS) and nitric oxide (NO) [107‐109]. These findings underscore the importance of glucose metabolism in conjunction with inflammation in the pathophysiology of AD.

Inflammatory stimuli, such as exogenous Aβ or lipopolysaccharides (LPS), have also been shown to reduce the oxidative metabolism of macrophages and microglia. This is accomplished through the activation of inflammatory cascades, resulting in inefficient metabolic glycolysis [110, 111]. Notably, a study involving a 76-year-old subject demonstrated a 28% decrease in TCA-cycle activity in neurons, while astrocytic TCA-cycle activity increased by 30% compared to a 26-year-old subject, highlighting alterations in neuro-glial metabolic flux [112].

In addition to these metabolic shifts, cultured microglia from APP/PS1 mice (a transgenic AD model) exhibited disrupted phagocytosis and chemotactic activity alongside elevated glycolytic rates, indicating a neuroimmunomodulatory phenotype that may affect AD pathophysiology [97].

Genome-wide association studies (GWAS) have identified several genetic risk factors associated with AD, notably variations in the APOE4, TREM2, and TLR4 genes. These genes, which are implicated in metabolic processes, are primarily expressed in microglia. For instance, the APOE gene has been shown to influence Aβ peptide production in transgenic AD mice via astrocytic cholesterol [113, 114]. The APOEε4 allele, in particular, is associated with a significantly heightened risk of developing AD, with homozygous carriers facing up to a 15-fold increased risk [100, 115, 116]. PET scans of young individuals carrying the APOEε4 allele revealed reduced glucose metabolism in the cerebral cortex, mirroring patterns observed in older AD patients [100, 117]. Furthermore, Ding and colleagues (2013) reported that hexokinase, a crucial enzyme in glucose metabolism, was downregulated in the brains of APOEε4 carriers compared to those with APOEε2 or APOEε3 alleles [118]. This downregulation led to impaired glucose metabolism, linked to the suppression of the PPAR-γ/PGC-1α signaling pathway, which is associated with AD pathogenesis [119, 120]. TREM2, another key player in AD, is expressed on microglia and has been shown to bind Aβ oligomers, facilitating the clearance of amyloid peptides from the healthy brain. Functional mutations or deficiencies in TREM2 have been linked to increased AD risk [121, 122]. Recent research demonstrated that TREM2 deficiency results in elevated cholesterol ester levels, exacerbating inflammation and burdening microglial phagocytic functions [123]. Microglia from TREM2 − / − /5XFAD mice displayed decreased glycolysis and ATP synthesis, coupled with increased autophagy, due to mTOR signaling pathway malfunctions [124]. The impairment of TREM2-mTOR signaling in AD patients correlates with fewer activated microglial cells surrounding amyloid plaques. Additionally, TREM2 knockout has been shown to elevate tau phosphorylation, leading to microglial activation in AD mice. Surprisingly, TREM2 haploinsufficiency exacerbates tau pathology and inflammatory responses more than full TREM2 knockdown in tauopathy models, indicating a nuanced role for TREM2 in regulating neuroinflammation [125, 126].

Hypoxia signaling pathways have also been implicated in the metabolic disturbances and pro-inflammatory states characteristic of AD [127, 128]. TLR4, in particular, has been highlighted for its role in the immunometabolism of Aβ-treated microglial cells via the mTOR-HIF-1α hypoxia signaling pathway. Aβ induces mTOR phosphorylation and HIF-1α production in primary microglia, activating pro-inflammatory pathways [128]. Increased mTOR-HIF-1α signaling correlates with reduced oxygen consumption and elevated extracellular acidification rates, significantly altering the glycolytic balance in these cells [124]. These observations underscore a critical neuroimmunometabolic imbalance associated with lipid and sugar metabolism that likely contributes to the pathophysiological condition’s characteristic of AD.

In conclusion, the multifaceted interactions between neuroinflammation, immunometabolism, and genetic factors underscore the complexity of AD. The intricate relationship between metabolic disruptions and inflammatory processes offers valuable insights into the pathogenesis of AD and highlights potential therapeutic avenues. Continued exploration of these interconnected pathways may pave the way for innovative strategies to mitigate the progression of this devastating disease. Understanding the roles of specific genes and metabolic alterations, particularly in microglia and astrocytes, could lead to targeted interventions aimed at restoring metabolic balance and reducing neuroinflammation in AD patients. This holistic approach may ultimately enhance our ability to treat and manage AD more effectively.

AD is a complex neurodegenerative disorder characterized by the accumulation of Aβ plaques, neurofibrillary tangles, neuroinflammation, and progressive cognitive decline. Recent research has illuminated the significant role of the fibrinolytic system, particularly fibrinogen, in the pathogenesis of AD. The fibrinolytic system is crucial for maintaining healthy blood vessel function and regulating fibrin formation, which is vital for various biological processes such as wound healing, tissue remodeling, and inflammation [129‐131]. The fibrinolytic system consists of several key proteins, including plasminogen, urokinase plasminogen activator (uPA), and tissue plasminogen activator (tPA). Plasminogen is activated into plasmin by serine proteases like tPA and uPA. The plasmin produced plays a critical role in dissolving fibrin clots, which helps to prevent excessive blood clot formation that can obstruct blood flow and lead to tissue damage. Fibrinogen, a key component of the fibrinolytic system, is particularly noteworthy for its interactions with cellular prion protein (PrPC) in the context of neuroinflammation. The binding of fibrinogen to PrPC results in the overexpression of tyrosine receptor kinase B (TrkB) in astrocytes, which subsequently leads to the production of reactive oxygen species (ROS) and nitric oxide (NO) [132, 133]. These molecules induce oxidative stress, which has been implicated in neurodegeneration. Furthermore, when fibrinogen binds to receptors on astrocytes such as intercellular adhesion molecule-1 (ICAM-1) or PrPC, it triggers the upregulation of inflammatory cytokines, including IL-6, CXCL-10, and CCL2. This cascade of events ultimately results in oxidative stress and the death of astrocytes [134]. Fibrinogen also can transport an inactive form of transforming growth factor-β (TGFβ), which becomes activated upon interaction with astrocytes. This process can contribute to the inflammatory environment observed in AD. Research has demonstrated that fibrinogen inhibits neurite development by acting as a ligand for the β3 integrin receptor on neurons. This interaction not only prevents neurite outgrowth, but also causes the phosphorylation and aggregation of the epidermal growth factor receptor (EGFR), further inhibiting neurite development [135]. The implications of these findings suggest that fibrinogen's effects on neuronal development are detrimental, particularly in the context of AD, where synaptic loss is a critical feature. Moreover, fibrinogen directly interacts with neurons, activating the NF-κB transcription factor and promoting the overexpression of inflammatory cytokines such as CCL2 and IL-6. This results in an amplified neuroinflammatory response, further exacerbating neuronal damage [134]. The stimulation of ROS, nitrite, and mitochondrial superoxide production in neurons leads to increased oxidative stress, ultimately resulting in apoptosis and neuronal cell death [134]. Co-culture studies have indicated that fibrinogen-induced astrocyte activation leads to increased neuronal apoptosis, demonstrating the interconnected nature of astrocytic and neuronal health [133, 134]. Notably, inhibiting the actions of ICAM-1 or PrPC may reduce the detrimental effects of fibrinogen on neurons, offering potential therapeutic targets.

In recent years, neuroinflammation has emerged as a crucial factor in the development and progression of AD. A well-established hallmark of AD is the accumulation of fibrinogen in the brain, particularly around cerebral blood vessels. This accumulation is frequently associated with cerebral amyloid angiopathy and is linked to changes in perivascular brain tissue [24, 76, 136]. Key pathological features of AD, including amyloid plaque formation, microglial activation, pericyte loss, and dystrophic neurites, are closely associated with fibrinogen deposition [24, 75, 89, 137]. Elevated fibrinogen levels have been observed in the plasma and CSF of AD patients, and these levels correlate with brain atrophy [138]. The leakage of fibrinogen into the brain parenchyma can result in fibrin deposition, which is associated with neurodegeneration and may negatively impact cognitive function. Studies have shown that fibrinogen co-localizes with areas of synaptic dysfunction in AD patients [139]. Moreover, lowering fibrinogen levels in animal models of Alzheimer's disease, such as TgCRND8 mice, has been shown to improve synaptic function, reduce Aβ deposition, and decrease neuronal death. These results indicate that targeting fibrinogen may present a promising therapeutic strategy for AD as shown in Fig. 5. Additionally, fibrinogen is known to activate microglia, leading to dendritic loss and spine elimination. This cascade contributes to neuroinflammation, synaptic dysfunction, and cognitive decline in 5XFAD mouse models [140]. Studies have shown that AD mice with impaired fibrin breakdown due to a lack of tPA or a single functioning plasminogen gene exhibit increased Aβ plaque accumulation, vascular damage, and cognitive impairment [141]. Importantly, damage to the blood–brain barrier (BBB) was significantly reduced in AD mice with just one functioning fibrinogen gene [141]. The interaction between fibrinogen and Aβ has been shown to have significant implications for AD pathology. The central region of Aβ can bind to specific domains on the fibrinogen protein, resulting in the formation of more robust and resistant fibrin networks [24]. This binding not only promotes the synthesis of Aβ fibers, but also increases the spatial extent and duration of fibrin clots within the brain [139, 142, 143]. These alterations may contribute to fibrin-induced neurotoxicity and microglial activation, amplifying the pathogenesis of AD [75, 144]. Furthermore, Aβ has been shown to interact with coagulation factor XII, leading to the activation of factor XI, thrombin production, and the formation of fibrin clots [24, 143]. Additionally, Aβ enhances the cleavage of high molecular weight kininogen (HK) via an FXII-dependent pathway [145]. Research has demonstrated that blocking HK cleavage reduces neuroinflammation, fibrinogen deposition, neuronal degeneration, and cognitive decline in AD models [146]. The accumulation of fibrinogen in the brain following vascular injury appears to be a significant pathogenic component that exacerbates inflammation and contributes to the onset and progression of AD. Targeting fibrinogen and its interactions within the fibrinolytic system may present novel therapeutic avenues for mitigating the inflammatory processes associated with AD. Therapeutic strategies that focus on reducing fibrinogen levels, inhibiting its interaction with neuronal receptors, or promoting fibrinolysis may enhance cognitive function and slow the progression of neurodegeneration. For instance, the use of agents that enhance the activity of tPA could facilitate the breakdown of fibrin deposits, thereby alleviating neuroinflammation and improving neuronal health.

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The fibrinolytic system, particularly the role of fibrinogen, is intricately linked to the pathophysiology of AD. By elucidating the mechanisms through which fibrinogen influences neuroinflammation, neuronal health, and cognitive function, researchers can identify potential therapeutic strategies aimed at mitigating the effects of this protein in AD. Ongoing research is essential to further understand the complex interplay between fibrinogen, neuroinflammation, and cognitive decline, ultimately guiding the development of effective treatments for AD. As our understanding of these relationships deepens, new therapeutic opportunities may arise to better manage this devastating condition.

In the AD treatment, traditionally, research has concentrated on canonical targets such as Aβ and hyperphosphorylated tau protein, which are central to the amyloid cascade hypothesis. Aβ, resulting from the cleavage of APP, accumulates in the brain, forming plaques that disrupt synaptic function and trigger neuroinflammation [147]. Concurrently, the tau protein forms neurofibrillary tangles through hyperphosphorylation, leading to microtubule instability and neuronal death [148]. Therapeutic strategies targeting these canonical pathways include monoclonal antibodies designed to reduce Aβ levels, such as aducanumab, and small molecules aimed at inhibiting tau phosphorylation. Although some of these therapies have shown promise in clinical trials, they often encounter significant limitations, including variable efficacy in advanced stages of the disease and potential adverse effects, underscoring the need for a more comprehensive approach that addresses the multifactorial nature of AD [149, 150].

In contrast to these canonical targets, non-canonical targets encompass a wider array of mechanisms that are increasingly recognized as crucial in AD pathology. One significant aspect of non-canonical targets is neuroinflammation. Chronic inflammation mediated by activated microglia and astrocytes has been implicated in AD progression, contributing to neuronal damage [151]. Targeting neuroinflammation through anti-inflammatory agents or immune-modulating therapies presents a promising strategy for restoring CNS homeostasis and mitigating neurodegenerative processes [152]. Furthermore, metabolic dysfunction has emerged as another critical non-canonical target. Research suggests that disturbances in cellular metabolism, particularly in energy production and glucose metabolism, can exacerbate AD pathology [153, 154]. Interventions that enhance mitochondrial function or promote alternative energy sources, such as ketogenic diets, have shown the potential to improve cognitive function and address the energy deficits commonly observed in AD patients [155].

Another important consideration is the role of vascular health in AD pathology. Vascular contributions, including blood–brain barrier (BBB) dysfunction and reduced cerebral blood flow, are increasingly recognized as critical factors in AD development [156]. Preserving BBB integrity and improving cerebral perfusion can mitigate neuroinflammatory responses and enhance the delivery of therapeutic agents to the brain. Strategies aimed at promoting endothelial health or stabilizing the BBB offer innovative therapeutic avenues that extend beyond classical targets. Additionally, glial cells, particularly oligodendrocytes and astrocytes, play vital roles in supporting neuronal health and synaptic function. Enhancing glial cell functionality could provide a protective effect against neurodegeneration. For instance, therapies focused on promoting oligodendrocyte myelination or supporting astrocyte-mediated neurotransmitter recycling could have significant implications for cognitive function and overall brain health [157].

The interplay between canonical and non-canonical targets is crucial in understanding AD’s complex pathology. For example, neuroinflammation can exacerbate tau pathology, while metabolic dysfunction may influence glial cell activation and overall neuronal health [158]. This interconnectedness highlights the potential for synergistic therapeutic effects when targeting multiple pathways simultaneously. Combination therapies that address both canonical and non-canonical targets may provide a more effective strategy for managing AD. For instance, interventions that lower Aβ levels while simultaneously enhancing glial cell function could yield superior outcomes compared to targeting either pathway alone [159]. Such integrative approaches are increasingly recognized as essential for personalized medicine in neurodegenerative diseases, acknowledging the multifactorial nature of AD.

In summary, while canonical targets such as Aβ and tau have historically dominated AD research, the exploration of non-canonical targets is essential for a nuanced understanding of the disease. Non-canonical pathways, including neuroinflammation, metabolic dysfunction, vascular health, and glial cell functionality, offer promising therapeutic avenues that address the broader spectrum of AD pathology. The integration of both approaches may lead to innovative interventions that improve patient outcomes. As research continues to advance, it is imperative to embrace a holistic perspective that considers the complex interplay of mechanisms driving AD, paving the way for effective therapies that genuinely address the needs of individuals affected by this devastating disease.