Aging-Related Protein Alterations in the Brain

Abstract

Aging is an intrinsic aspect of an organism’s life cycle and is characterized by progressive physiological decline and increased susceptibility to mortality. Many age-associated disorders, including neurological disorders, are most commonly linked with the aging process, such as Alzheimer’s disease (AD). This review aims to provide a comprehensive overview of the effects of aging and AD on the molecular pathways and levels of different proteins in the brain, including metalloproteins, neurotrophic factors, amyloid proteins, and tau proteins. AD is caused by the aggregation of amyloid proteins in the brain. Factors such as metal ions, protein ligands, and the oligomerization state of amyloid precursor protein significantly influence the proteolytic processing of amyloid-β protein precursor (AβPP). Tau, a disordered cytosolic protein, serves as the principal microtubule-associated protein in mature neurons. AD patients exhibit decreased levels of nerve growth factor within their nervous systems and cerebrospinal fluid. Furthermore, a significant increase in brain-derived neurotrophic factor resulting from the neuroprotective effect of glial cell line-derived neurotrophic factor suggests that the synergistic action of these proteins plays a role in inhibiting neuronal degeneration and atrophy. The mechanism through which Aβ and AβPP govern Cu2+ transport and their influence on Cu2+ and other metal ion pools requires elucidation in future studies. A comprehensive understanding of the influence of aging and AD on molecular pathways and varying protein levels may hold the potential for the development of novel diagnostic and therapeutic methods for the treatment of AD.

Keywords

Alzheimer’s disease apoptosis brain-derived neurotrophic factor neurotrophic factors oxidative stress

INTRODUCTION

Alzheimer’s disease (AD) is a prevalent neurodegenerative dementia that has become an escalating global concern with the aging of the world population. The significant increase in life expectancy has contributed to the growth of the elderly population. In 2020, the percentage of individuals aged 65 years and older rose from 6.9% in 2000 to 9.3% worldwide [1]. It is estimated that by 2030, 1 in 6 individuals worldwide will be aged 60 or older, amounting to 1.4 billion people, an increase from 1 billion in 2020. This number is projected to double to 2.1 billion by 2050 [2]. However, the rise in the number of older individuals, attributed to longer lifespans, has led to a substantial increase in the incidence of age-related disorders, with dementia, most commonly AD, emerging as a major concern [3]. Globally, AD accounts for 60–80% of dementia cases; it affected 50 million individuals in 2020 and is anticipated to double by 2050 [4, 5].

AD is the most prevalent and severe type of dementia, characterized by a decline in two or more cognitive abilities, often accompanied by persistent and gradual memory loss [6, 7]. Physiological aging is the natural process of increasing age, resulting in normal changes in the brain, including subtle cognitive alterations such as a decline in memory, which is expected as people age. Pathological aging, as defined by conditions such as AD, signifies the presence of aberrant, disease-driven modifications in the brain. This type of aging leads to significant cognitive loss that exceeds normal age-related changes [8, 9]. Key neuropathological features include gross atrophy of the cortex and hippocampus, the accumulation of amyloid-β (Aβ) in senile plaques, and the hyperphosphorylation of tau, resulting in the formation of neurofibrillary tangles (NFTs) [10].

AD is a complex disorder characterized by various inflammatory factors, including genetic contributors such as amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1/2), which have been identified as significant risk factors for AD. Approximately 40% of familial AD cases result from mutations in PSEN1 and PSEN2 [11]. The identification of pharmacological targets capable of influencing the trajectory of age-related cognitive decline is therefore urgently needed [7].

In recent years, proteins and receptors have emerged as potential targets for drug development, contributing to the understanding of mechanisms associated with dementia. Consequently, this review aims to provide an overview of the effects of pathological aging, particularly in AD, on various molecules (such as metalloproteins and neurotrophic factors), cellular processes (such as inflammation and apoptosis), and the levels of different proteins (amyloid proteins and tau proteins) within the brain.

AMYLOID-β PROTEIN PRECURSOR (AβPP)

AβPP, a single-pass transmembrane protein, is abundantly expressed in the brain and undergoes intricate metabolism through a series of proteases, including the intramembranous γ-secretase complex. In AD patients, AβPP accumulates in the brain alongside tau protein, playing a pivotal role in AD pathogenesis (Fig. 1) [12]. The sequential action of α- and γ-secretases cleaves AβPP, resulting in the formation of Aβ, which forms insoluble peptides that aggregate to create Aβ plaques, leading to the deterioration of brain cells [13]. Point mutations and duplications of AβPP are responsible for the early onset of familial AD [11]. In healthy brains, β-secretase enzymes cleave Aβ to form soluble AβPP fragments. The remaining AβPP undergoes further breakdown by β-secretase, forming peptides that are subsequently eliminated from the body. However, secretase homeostasis is dysregulated in AD, causing AβPP to be cleaved by both β- and γ-secretases, resulting in the formation of insoluble Aβ plaques [12].

Fig. 1

Processing of amyloid-β protein precursor (AβPP) contributes to the pathogenesis of Alzheimer’s disease. In the nonamyloidogenic pathway, AβPP is cleaved by α-secretase, yielding extracellularly released soluble AβPP (left). In the amyloidogenic pathway, AβPP is cleaved by β-secretase, followed by γ-secretase (right). This process leads to the release of extracellular Aβ, which is prone to self-aggregation, ultimately resulting in the formation of cytotoxic oligomers and insoluble Aβ fibrils/plaques.

According to genetic, biochemical, and behavioral research, the critical stage in the onset of AD is the physiological synthesis of the neurotoxic peptide Aβ through sequential AβPP proteolysis [11]. Neurotoxic Aβ is produced when AβPP undergoes abnormal proteolysis, a complex process influenced by various factors such as metal ions, protein ligands, and the AβPP oligomerization state. Cu2+ and Zn2+ may interfere with Aβ metabolism while promoting AβPP expression [14]. Cu2+ improves AβPP dimerization and facilitates Aβ release into the extracellular space [15]. However, some research has suggested that high Cu2+ concentrations may alter AβPP processing and decrease Aβ synthesis [16]. The binding of metal ions induces significant conformational changes and diverse structural states, thereby exerting control over AβPP and Aβ metabolism [17].

Studies have demonstrated that AβPP loaded with Cu2+ can lead to cell death in primary neuronal cultures, potentially acting as a mediator of copper neurotoxicity [18, 19]. This process might involve the catalytic conversion of Cu2+ to Cu+, which could enhance neuronal oxidative stress. Furthermore, the interaction of AβPP with ferroportin to increase iron export and ferroxidase activity emphasizes the intricate connections between AβPP and metal metabolism. The inhibition of AβPP ferroxidase activity by Zn2+ binding results in the accumulation of Fe2+ in the AD brain [20, 21].

In the normal physiological process, AβPP is processed into amyloidogenic and nonamyloidogenic products, and the development of Aβ aggregates is substantially influenced by the interaction of AβPP with cell adhesion molecules.

TAU PROTEIN

Tau, a disordered cytosolic protein, serves as the primary microtubule-associated protein (MAP) in mature neurons. Alongside tau, MAP1 and MAP2 are the other two significant neuronal MAPs. The interaction between MAPs and tubulin promotes the formation of microtubules and stabilizes the microtubule network [22]. Particularly, tau can facilitate microtubule assembly and maintain structural integrity. While the aging brain may experience physiological changes in tau levels, they may not lead to the severe tau pathology observed in AD. However, in AD, tau processing involves pathological hyperphosphorylation and aggregation into NFTs [23].

In the normal adult human brain, tau contains 2-3 moles of phosphate per mole of tau protein [24]. In AD and other tauopathies, tau becomes substantially more phosphorylated, with roughly nine phosphates per molecule [25]. A threefold increase in tau phosphorylation compared to healthy adult brain tau is indicative of AD, hindering the normal functioning of tau [26]. Under hyperphosphorylated conditions, tau undergoes polymerization into paired helical filaments mixed with straight filaments, forming NFTs (Fig. 2) [24]. Hyperphosphorylation triggers tau aggregation, leading to the accumulation and deposition of tau protein aggregates in the brain [25]. This process causes the development of intracellular tau-paired helical filaments, which eventually merge to form distinctive NFTs [27]. The abnormal phosphorylation of tau in AD leads to the loss of synapses and neurons in the brain, a process regulated by metal ions [18].

Fig. 2

The pathological process of tau pathology in Alzheimer’s disease. The hyperphosphorylation (denoted as “P”) of the tau protein leads to destabilization of the tau–tubule complex and the assembly of the tau protein into higher-order aggregates. Hyperphosphorylated tau detaches from microtubules and aggregates to form paired helical filaments and neurofibrillary tangles.

METALLIC IONS AND METALLOPROTEINS

The pathogenesis of AD is directly linked to dynamic imbalances in metal ions, including Zn2+, Fe3+, Ca2+, and Cu2+, in the brain [19]. The proportion of free metal ions in the brain is minimal and has no significant impact on neurological functions under normal circumstances. However, in the brain tissues of AD patients, transition metal ions, namely Zn2+, Fe3+, and Cu2+, are abundant [28]. These metal ions are closely correlated with the phosphorylation of tau, accumulation of Aβ, generation of reactive oxygen species (ROS), and neuronal loss [29].

Zinc

Zinc (Zn2+), an essential trace element, plays a role in various physiological processes, including the synthesis of nucleic acids and proteins, as well as immunological modulation [30]. The differentiation of neural stem cells and the development of the nervous system both depend on the appropriate influx of Zn2+. Imbalances in Zn2+ homeostasis have been linked to several neurodegenerative diseases [31]. Zn2+ can bind to tau and promote its hyperphosphorylation. In regions with a high density of glutamatergic neurons, tau dysfunction is more likely to occur due to the potential of zinc to inhibit protein phosphate activity. Excitation-mediated zinc release from glutamate neurons leads to an increase in tau pathology [32]. Zn ions can facilitate the accumulation of the Tau protein, ultimately resulting in cytotoxicity [33].

Zn2+ transporters, namely ZnT1, ZnT4, ZnT6, LIV1, and ZIP1, show increased mRNA levels in the cortex of postmortem brain tissues from AD patients. This increases the possibility of interactions between Zn2+ and Aβ or tau protein in the brain [34]. The synaptic Zn2+ transporter zinc transporter 3 (ZnT3) is responsible for converting zinc into presynaptic vesicles. In AD transgenic mice, high levels of the ZnT3 protein, which colocalizes with amyloid plaques, are observed [35, 36]. The effect of Zn on Tau pathogenesis is further supported by the finding that excessive Zn supplementation can induce cognitive impairment and tau protein phosphorylation in transgenic mice harboring human tau protein [37]. Hence, tau aggregation is believed to be caused by aberrant Zn2+ homeostasis.

Iron

Iron (Fe), a metallic element, is crucial in the brain as it plays essential roles in neurotransmission, oxygen transport in cells, and DNA synthesis [38]. Its efficient electron transfer properties, allowing it to switch between ferric, divalent, and tetravalent iron states, play a critical role in various metabolic processes as a catalytic cofactor [39]. However, iron accumulates in specific brain regions, such as the globus pallidus, cortex, dentate nucleus, red nucleus, and substantia nigra, with aging [40]. This accumulation of iron can lead to the activation of the Fenton reaction, generating hydroxyl radicals that damage DNA, cell lipids, and proteins, ultimately resulting in cell death [41].

Excessive iron levels have been associated with an increased risk of AD, contributing to the production of NFTs and the deposition of Aβ [42]. Iron can act on the iron-responsive element site of AβPP mRNA, increasing the translation and expression of endogenous AβPP, thus promoting the emergence and accumulation of the peptide Aβ [43]. In vitro studies have revealed that iron can exacerbate the aggregation of Aβ peptides, increasing their cytotoxicity [44]. AβPP and Aβ have been shown to interact with both Fe2+ and Fe3+, promoting the accumulation of Aβ in fibrillar forms [45]. In contrast to zinc and copper, the interaction of the amino acids of Aβ proteins with Fe2+ can induce specific structural modifications in amyloids [45]. The reduction of Fe3+ coupled to Aβ to Fe2+ enhances the generation of ROS, which in turn leads to neuronal death by promoting secretase cleavage of Aβ₄₂ monomers into more damaging Aβ oligomers [46]. Aβ plaques can disrupt mitochondrial function, inducing oxidative stress and facilitating the conversion of Fe3+ to Fe2+, thereby exacerbating the accumulation of iron and worsening the state of AD [47].

NFTs, primarily composed of phosphorylated tau protein, represent another significant pathogenic aspect of AD. Studies have shown that NFT-containing neurons are sites of iron accumulation [48]. Iron plays a significant role in the accumulation and formation of hyperphosphorylated tau protein in NFTs [45]. It is involved in the hyperphosphorylation of the tau protein [48, 49], activating the cyclin-dependent kinase-5/P25 complex and glycogen synthase kinase-3 [50].

Ferritin, a protein responsible for storing iron, is essential for iron homeostasis. Iron prevents potentially harmful effects on proteins, lipids, and DNA while making iron available for essential cellular functions [49]. In AD, higher concentrations of ferritin are found in brain tissues, and its presence around Aβ plaques suggests that ferritin trapped within plaque inclusions may hinder the passage of iron between cells [49, 51]. AD patients have been associated with decreased ferroportin protein levels and increased ferritin, leading to the loss of hippocampal tissue integrity [52].

Copper

Copper (Cu) is an essential trace element crucial for the development of the nervous system. However, its role in AD is complex. Copper has been implicated in the onset of AD through its interaction with Aβ plaques, leading to the generation of ROS [53]. Copper, involved in cycles between +1 and +2 oxidative states, can increase ROS levels when attached to plaques, causing damage to proteins, lipids, DNA, and RNA, potentially accelerating the aging process and contributing to AD [54].

Cu2+ ions have a strong affinity for Aβ peptides, and their binding can lead to Aβ accumulation, particularly by increasing the ratio of β-sheet and α-helix structures in amyloid peptides [55]. Different concentrations of Cu2+ ions can enhance the development of fibrils, increasing cellular toxicity [56]. The brains of AD patients have lower levels of total copper while having higher levels of labile copper in the most damaged areas of the brain [57]. Moreover, both the cortices of mice with acute brain injury and the cortical tissues of AD patient’s exhibit increased Cu2+ binding ability [58].

In vitro experiments have demonstrated that Cu2+ binding to Aβ results in the development of Aβ dityrosine-linked dimers in AD [59]. Copper can also enhance the release of proinflammatory molecules such as interleukin (IL-6) and downregulate the expression of lipoprotein receptor-related protein-1 (LRP1) and tumor necrosis factor-α (TNF-α), thereby increasing brain inflammation [60]. These findings suggest that the potential of copper to promote inflammation may play a role in the progression of AD.

Calcium

The pathophysiology of AD is often associated with calcium imbalance [61]. Presenilin mutations can disrupt intracellular calcium homeostasis through various pathways, such as inhibiting presenilin-mediated calcium release [62], affecting calcium entry [63], and increasing the expression of the ryanodine receptor, transient receptor potential canonical channels, and inositol trisphosphate receptors [64]. The connection between Ca2+ homeostasis and presenilin is further supported by mutations in presenilins found in familial AD cases, which can lead to the downregulation of Ca2+ channels, altered Ca2+ dependency [65], and altered mitochondrial transport proteins [21].

Additionally, presenilin genetic deletions and familial AD mutations have been associated with abnormal Ca2+ signaling [63]. This disruption in calcium homeostasis may play a significant role in the pathogenesis of AD.

NEUROTROPHIC FACTORS (NTFs) AND THEIR ROLE IN AD

NTFs are endogenous proteins that play a significant role in activating genes involved in brain repair during neurodegeneration. These small, adaptable proteins are crucial for the development of memory and cognition, neuronal survival, maintenance of cell shape, and guidance of axons [66]. NTFs are essential for maintaining the proper structure and function of the brain throughout all stages of embryonic development. Following neuronal trauma, such as cerebral ischemia, NTF levels increase, and NTF plays a role in neurogenesis and healing [67]. NTFs regulate the survival, neurite outgrowth, synapse formation, migration, and neural plasticity of neurons [68]. By modulating intracellular signaling through specific receptors, NTFs play a significant role in neural regeneration, remyelination, and the development of the peripheral nervous system (PNS) and central nervous system (CNS) [69, 70].

The NTF superfamily includes various neurotrophins, neuroinflammatory cytokines, glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), mesencephalic astrocyte-derived neurotrophic factor family members, family ligands (GFLs), nerve growth factor (NGF) family members, brain-derived neurotrophic factor (BDNF), fibroblast growth factor, epidermal growth factor, GP130-binding growth factor family members such as Ciliary neurotrophic factor (CNTF), insulin-like growth factor, heparin-binding growth factor, and transforming growth factor family members. These factors have been shown to change with age in both human and rodent models. Reduced levels of certain factors have been linked to age-related illness in the brain [71]. Changes in neurotrophic factors and their receptors have been proposed as contributing factors to human neurodegenerative disorders [72 –74], including AD [71].

The lack of expression of neurotrophin proteins or receptors may contribute to AD. In the brains of AD patients, nerve growth factor levels increase in the hippocampus and some neocortical regions, BDNF levels decrease, and TrkA levels decrease in the cortex and nucleus basalis [75].

Nerve growth factor

NGF is a glycoprotein consisting of three subunits: α-NGF, β-NGF, and γ-NGF. NGF can be secreted from cells or converted intracellularly into mature NGF and is synthesized as a precursor known as Pro-NGF. In the CNS, pro-NGF is predominant and secreted simultaneously with mature NGF [76]. NGF exerts its effects through three types of receptors: p75, TrkA, and sortilin. The TrkA and p75 receptors are involved in the trophic effect of NGF [77, 78], while sortilin and p75 are involved in the neurotoxic effects of pro-NGF [78]. Another NGF receptor is the low-affinity p75NTR, which promotes cell survival, growth inhibition, and cell death [78, 79]. NGF plays a critical role in promoting the survival and maintenance of neurons, as well as facilitating neurite and axonal outgrowth, expansion, and branching [77]. NGF is believed to regulate and direct neuronal growth, regeneration, differentiation, neurotransmitter function, development, and phenotypic maintenance in the PNS. NGF is present in the cell bodies of basal forebrain cholinergic neurons, the brain, and the olfactory bulb [80].

NGF levels have been reported to decrease in the nervous systems and cerebrospinal fluid (CSF) of AD patients [71]. Cholinergic degeneration is a hallmark of AD, suggesting an association between NGF and AD [81]. Cognitive impairment and dementia in AD patients are associated with the progressive degradation of the basal forebrain cholinergic system, which may result in NGF impairment [82, 83]. NGF levels were found to be greater in the dentate gyrus and CSF of AD patients than in those of a control group [71, 84]. Several intriguing investigations have suggested that NGF therapy for AD patients results in reduced levels of Aβ_1 - 42 in the CSF [85, 86].

Increased levels of pro-NGF have been associated with the induction of apoptosis in various cell types in relation to epilepsy and spinal cord injury [87, 88]. Furthermore, research has shown that pro-NGF inhibits the proliferation and differentiation of neural stem or progenitor cells in the hippocampus of postnatal mice [50]. These effects have been linked to abnormalities in recognition memory and spatial learning. In the prefrontal cortex and hippocampus of aged rats, these effects were accompanied by increased levels of pro-NGF, p75NTR, and sortilin [88, 89].

Growth factors, including NGF, are crucial for the survival and plasticity of forebrain cholinergic neurons, which are found in brain regions involved in memory, such as the cerebral cortex, hippocampus, hypothalamus, and basal forebrain. NGF may play a role in the age-dependent decline in cognitive performance, as it is essential for cognitive functions and has been reported to decrease with age [90]. Therefore, NGF is important for memory and cognition as well as for the growth, survival, and maintenance of cholinergic neurons typically found in the aging brain [91].

Brain-derived neurotrophic factor

BDNF is a crucial protein involved in the neuroplastic changes associated with memory and learning. It is essential for promoting the growth and maturation of neurons during development and regulates synaptic plasticity in adults [92, 93]. BDNF is crucial for the development and maintenance of synapses, promoting neuron survival, inducing neuroplasticity, and enhancing cognitive function in the aging brain [94]. It is expressed in various brain tissues, and its expression in the CNS and PNS can be influenced by factors such as nutrition, metabolism, behavior, and stress [95]. BDNF is synthesized from the pro-isoform of BDNF and is proteolytically cleaved (the N-terminal region/terminal region is eliminated), typically within the neuron or after release, to generate its mature form [96]. BDNF acts on tropomyosin-related kinase (TrkB) receptors, which are protein kinase neurotrophin receptors [97]. BDNF plays a significant role in regulating various neuronal processes, such as long-term depression, long-term potentiation, axonal sprouting, synaptic plasticity, dendritic arbor proliferation, and neuronal differentiation, making it essential for learning and memory [98]. These CNS processes are triggered by the interaction of BDNF with TrkB receptors [97].

BDNF stimulates signal transduction cascades, including those involving Akt, PI3K, and IRS1/2, which are necessary for the synthesis of cyclic adenosine monophosphate response element binding protein (CREB) (Fig. 3). CREB encodes proteins that are essential for the survival of β-cells and are bound to the TrkB (tyrosine kinase-B) receptor [99]. The p75 neurotrophin receptor (p75NTR) binds to pro-BDNF and activates apoptotic pathways in peripheral neurons and glia [100]. The activation of PI3K initiates when the TrkB receptor is activated by mature BDNF and autophosphorylated tyrosine residues, promoting neuronal development and providing trophic support to neurons [75]. The BDNF-TrkB pathway is an essential signaling pathway for the biological function of BDNF, and the loss of this pathway may play a key role in various neurodegenerative disorders, including AD and Parkinson’s disease (PD).

Fig. 3

BDNF signaling pathway and downstream signaling cascades. BDNF stimulates a cascade of signal transduction events, which include Akt, PI3K (phosphatidylinositol 3 kinase), and phospholipase C-gamma (PLCγ). Upon binding, BDNF autophosphorylates tyrosine residues in the intracellular C-terminal domain, subsequently triggering the activation of second messenger signaling pathways, such as PLCγ, MAPK (mitogen-activated protein kinase), and PI3K, which are essential for the synthesis of cyclic adenosine monophosphate response element binding protein (CREB). These downstream pathways are associated with various processes, including cell adhesion and migration, cell survival, synaptic plasticity, neurogenesis, and neuronal differentiation.

BDNF plays a crucial role in supporting the basal forebrain cholinergic system, which is involved in memory and cognition. The decrease in BDNF levels may be a potential contributing factor to the progressive atrophy of basal forebrain cholinergic neurons in AD [101,102, 101,102]. BDNF may be involved in regulating cell death (apoptosis) in AD [103]. BDNF mRNA levels are reduced in the hippocampus of individuals with AD [104]. Treatment with BDNF attenuates cognitive dysfunction, prevents synaptic loss, repairs Aβ-induced damage, reduces aberrant Aβ production, mediates cell death, and delays cognitive decline in AD [105, 106]. A recent meta-analysis reported that AD patients have lower serum levels of BDNF mRNA and protein [107]. Additionally, BDNF stimulation has been associated with tau dephosphorylation in neuronal cells, particularly in the common AT8 region associated with AD [108].

The infusion of exogenous BDNF resulted in significant functional alterations in the locus coeruleus (LC) and a decreased threshold current, while no morphological alterations were observed in the noradrenergic axons [71]. This finding suggested that BDNF may play a role in functional alterations in the presynaptic axon terminals of LC neurons in the aging brain [109]. BDNF signaling has downstream effects that significantly modulate amyloid buildup in AD [106]. BDNF regulates the release of gamma amino-butyric acid (GABA) and glutamate neurotransmitters and activates nuclear factor-kappa B (NF-κB), which is particularly involved in linking neuroplasticity and inflammation [110]. Patients with AD have lower levels of BDNF in their brains [111], CSF [112], and blood [107]. Moreover, increased cognitive performance in individuals with AD has been associated with higher blood levels of BDNF [113]. Therefore, BDNF could serve as a potential biomarker for diagnosis and treatment. These findings indicate that BDNF may play a role in the pathophysiology of AD and could be a target for therapeutic interventions.

Glial cell line-derived neurotrophic factor

GDNF is crucial for the development, survival, and maintenance of midbrain dopaminergic neurons, playing a significant role in facilitating catecholaminergic neurons and considered important in neurodegenerative diseases such as AD, characterized by damage to cholinergic CNS neurons [114]. The neuroprotective effects of GDNF in brain aging may facilitate the delay of cognitive decline [71]. Various neuronal populations, including brainstem noradrenergic neurons, Purkinje cells, and dopaminergic neurons, contribute to the production of GDNF in the substantia nigra. The hippocampus also exhibits high levels of GDNF and its receptor expression from early embryonic stages to adulthood [115]. GDNF interacts with multiple component receptor complex compounds, including the cell surface GDNF receptor alpha1 (GFRα1) and the signaling component receptor tyrosine kinase (RET) [116].

Studies have shown that GDNF levels are decreased in plasma but elevated in CSF from patients with mild cognitive impairment and AD [117, 118]. However, the exact role of GDNF in AD is not yet fully understood. It has been suggested that GDNF may be crucial for protecting neurons from atrophy and degeneration [119]. Overexpression of GDNF led to enhancements in learning and memory [119, 120]. Age-dependent changes in LC noradrenergic innervation have been associated with an increase in GDNF expression in the frontal cortex. However, this increase was not observed in the hippocampus, suggesting that various neurotrophic factors may locally control these interventions, acting on different target sites trophically [121]. GDNF has been shown to have trophic and protective effects on peripheral motor neurons, noradrenergic neurons in the LC, glial cells, and neurons, protecting them from oxidative stress and damage [114].

The interaction between GDNF and its receptors plays a complex role in AD and potential treatment approaches. GDNF has been shown to regulate GFRα1 expression in normal neurons [116]. RET is a tyrosine kinase receptor that forms a transmembrane receptor complex with GDNF. Unlike the majority of receptor tyrosine kinases, RET cannot bind to ligands and requires a coreceptor, such as GFRα, which interacts with GDNF to form the GFL/GFR complex. This complex is crucial for RET activation. Once the GFL/GFR complex is formed, autophosphorylation and intracellular signaling are initiated, leading to downstream effects that are essential for the biological activities of GDNF and its receptors [122]. However, in the brains of patients with AD, GDNF fails to induce GFRα1 expression in cortical neurons [123]. A deficiency in GFRα1 expression, particularly associated with glutamatergic neurotransmission, provides insight into potential treatment approaches for AD through the increase in GFRα1 activity.

The depletion of GDNF has been associated with the pathology and symptoms of AD [119]. GDNF plays a critical role in the survival and maintenance of various types of neurons, including cholinergic neurons. Cholinergic neuron disturbances can contribute to the development of AD, given their importance in improving cognitive function. Research has indicated that there may be changes in GDNF levels in individuals with AD. Studies have shown higher levels of GDNF in the CSF and lower serum levels of GDNF in patients with early-stage AD. These findings suggest that the brain might be attempting to adapt to the damage caused by neurodegeneration [118]. Additionally, MCI and AD patients had considerably lower serum and higher plasma levels of GDNF [112]. However, the mature GDNF peptide was downregulated in specific brain regions, such as the middle temporal gyrus, of AD patients after death. This complex pattern of GDNF changes may be associated with the progression of the disease.

Furthermore, studies in animal models, such as 3xTgAD mice, have shown that GDNF has neuroprotective effects, resulting in the upregulation of BDNF. The simultaneous increase in GDNF and BDNF levels may work together to prevent neuronal atrophy and degeneration. This interaction could be a potential therapeutic target for preventing or slowing the progression of AD, especially in terms of preserving cognitive function [120]. Therefore, understanding the role of GDNF in the context of AD pathology provides valuable insights for potential treatment strategies and interventions aimed at protecting neurons and preserving cognitive function in individuals affected by AD.

Ciliary neurotrophic factor

CNTF belongs to the IL-6 family of cytokines and is renowned for its neuroprotective effects. CNTF acts as a survival factor for various types of neurons, including sympathetic, sensory, and hippocampal neurons [124]. It has demonstrated its capability to protect neurons from degeneration caused by various diseases [125]. However, its role in the context of AD pathogenesis has not been extensively studied. In a preclinical study, CNTF was continuously administered through microcapsules implanted in the brains of AD model mice. These microcapsules contained modified cells that secreted CNTF, preventing the behavioral and memory impairments induced by Aβ oligomers. The signaling pathways involved in the action of CNTF include the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and the phosphatidylinositol 3-kinase (PI3K) signaling pathway [126]. These pathways are essential for mediating the neuroprotective effects of CNTF.

Cerebral dopamine neurotrophic factor

CDNF, a member of the neurotrophic factor (NTF) family and a subclass within this family, is primarily localized in the endoplasmic reticulum [127]. Research on CDNF has revealed its potential neuroprotective and regenerative effects, particularly in the context of neurodegenerative diseases. In studies involving mouse models of neurodegenerative disorders like 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage, CDNF has demonstrated the ability to preserve dopaminergic cells. These protective effects were observed when CDNF was administered both before and weeks after inducing the lesion [128], highlighting its potential for protecting and restoring dopaminergic neurons [129]. Evidence supporting the reduction of cell damage and enhancement of nerve regeneration through CDNF overexpression has been obtained [130].

In the context of AD, where protein aggregation in the endoplasmic reticulum (ER) can lead to ER stress and neuronal cell death, CDNF is proposed to play a potential role in reducing ER stress, preventing neuronal death, improving cognitive function, and partially regenerating hippocampal neurons. Alongside a related protein called mesencephalic astrocyte-derived neurotrophic factor, CDNF has been implicated in these processes [130 –132].

ER stress and the unfolded protein response (UPR) are complex processes implicated in the pathogenesis of AD [133]. Understanding these processes is crucial for developing potential therapeutic interventions. Mild ER stress is believed to occur in the early stages of AD [133], and UPR activation is considered an adaptive and neuroprotective response to address ER stress [134]. Studies have suggested that UPR activation occurs in Aβ-induced early synaptic dysfunction, an early hallmark of AD [135]. CDNF has been shown to reverse the synaptic dysfunction associated with UPR activation, indicating a potential neuroprotective role in early-stage AD [136]. In advanced stages of AD, excessive and prolonged ER stress, also known as maladaptive UPR, becomes more common and contributes to disease progression by potentially exacerbating neuronal damage and cell death [133]. Studies have demonstrated that Aβ treatment increases levels of ER stress markers, including Bip/GRP78 and phosphorylated eIF2α, indicating that Aβ induces ER stress and activates the UPR. Additionally, proteins associated with ER stress, such as CHOP, phosphorylated JNK (pJNK), and cleaved caspase-3, are upregulated following Aβ treatment, suggesting that the UPR is activated in response to Aβ-induced stress [74]. Intracranial CDNF therapy improved long-term memory in experimental models [75]. However, the specific mechanisms through which CDNF exerts its neuroprotective effects in AD, particularly in the context of ER stress and the UPR, require further research and exploration.

NEUROINFLAMMATORY PROCESSES

Inflammation is increasingly recognized as a significant factor in the pathogenesis of AD, actively contributing to the disease’s progression and severity once initiated due to neurodegeneration or dysfunction. Numerous studies have demonstrated the crucial role of inflammation in AD pathogenesis [137, 138]. Neuroinflammation, the brain’s natural defense mechanism against injuries or infections, involves the activation of microglia and astrocytes, releasing various neuroinflammatory mediators. In AD, neuroinflammation is marked by pronounced and prolonged activation of inflammatory systems, with microglia, astrocytes, and neurons expressing and releasing inflammatory mediators, including complement activators, inhibitors, cytokines, radical oxygen species, chemokines, and inflammatory enzymes [140].

The degeneration of aminergic brainstem nuclei, such as the locus coeruleus and nucleus basalis of Meynert, can contribute to inflammation in projection areas [141]. These brainstem nuclei release major neurotransmitters like norepinephrine and acetylcholine, which have anti-inflammatory and neuroprotective effects [142]. Their degeneration may lead to a loss of these properties. While the typical aging brain exhibits some neuroinflammation, the AD brain shows significantly greater activation of inflammatory systems, suggesting the presence of more or qualitatively distinct immunostimulants. Dysregulation of various mediators and modulators of neuroinflammation, including cytokines (TNF-α, IL-1, IL-6, and IL-18), chemokines, prostanoids, caspases, neuroprotectin D1, and the complement system, plays a role in AD pathogenesis [143].

Unlike other risk factors and hereditary causes of AD, neuroinflammation is not considered a direct cause but typically emerges as a manifestation of other AD-related diseases and risk factors. Neuroinflammation exacerbates AD by aggravating Aβ and tau pathologies [137]. Elevated expression of markers associated with both innate and adaptive immune system responses is observed in the brains of AD patients [144, 145]. Toll-like receptor (TLR), alpha B crystallin, and gamma-aminobutyric acid play intriguing and unique roles in the immune system, modulating autoimmunity directed toward the brain [146]. Early-onset and familial AD are closely correlated with mutations in presenilin and amyloid precursor protein genes, encoding proteins involved in amyloid processing [11]. Aβ can trigger the innate immune system [147].

The pathogenesis and development of AD and PD involve the dysfunction of innate immune cells due to misfolded protein accumulation [144]. Research indicates that the regulation of microglial function, a pivotal element in AD or PD pathogenesis and progression, is governed by the TLR family [148]. Specific TLRs can detect protein aggregation in these diseases, implicating their role in disease development [149]. TLR4, for example, plays a significant role in AD pathogenesis, as evidenced by Aβ phagocytosis in APP/PS1 mice [152].

Recent genome-wide association studies have identified over 20 gene variants as risk factors for late-onset AD, the most prevalent form of the disease. These disease-modifying genes involve both innate and adaptive immune responses [139]. Altered peripheral innate immune cell function further facilitates the development and progression of AD and PD [144]. Multiple factors influence microglial activation in the AD brain, significantly affecting disease pathogenesis and progression. TLRs and their coreceptors, especially CD14 and CD36 [153, 154], play pivotal roles in microglia-mediated neuroinflammatory processes and the clearance of toxic Aβ forms. The NLRP3 inflammasome pathway is also crucial in this context. Elevated levels of proinflammatory cytokines such as IL-18, IL-1, and cleaved caspase-1 are found in the brain tissues of AD patients [155]. Susceptibility to developing AD is associated with specific polymorphisms in alleles related to IL-1, IL-1α, IL-1β, and the receptor accessory protein (IL-1RA), as identified in genome-wide association studies [156, 157].

TLRs are crucial in both innate and adaptive immunity, recognizing TLR ligands and initiating signaling events for pathogen eradication. Inappropriate inhibition or activation of these agents may result in negative side effects. Microglial dynamics change as the disease progresses; hence, targeting downstream signaling molecules in inflammatory diseases like AD may be a preferable approach to achieve significant and safe therapeutic effects.

Oxidative stress and the inflammatory response are critical components in AD pathogenesis [54]. The oxidative and inflammatory components of AD are linked to the transcription factor NF-κB, crucial in immunity and inflammation [159]. In animal models of neurodegeneration, including AD, NF-κB activation is associated with increased oxidative stress [160]. Alterations in perivascular neurons, glia, and cerebral blood vessels, triggered by vascular Aβ deposits and soluble Aβ oligomers, are associated with early-onset and chronic changes in AD. These changes result in reduced cerebral blood flow and impaired functional hyperemia, disrupting local blood flow associated with neuronal activation [162].

APOPTOSIS

Innate immune system cells not only contribute to pathogen elimination but also play a multifaceted role in the pathogenesis of AD, with microglia and astrocytes being significantly involved [163]. Upon activation, these innate immune cells can induce programmed cell death through various mechanisms, such as apoptosis, pyroptosis, PANoptosis, and necroptosis. The resulting cells often release proinflammatory cytokines, promoting the innate immune response and contributing to the elimination of Aβ plaques and aggregated tau proteins. Chronic neuroinflammation resulting from cell death has been associated with neurodegenerative diseases and can exacerbate AD [164].

The regulation of apoptosis is mediated by the B-cell leukemia-2 gene product (Bcl-2) family and the caspase family, which includes ICH-1 and CPP32 (Fig. 4). These proteins have been detected in membranous and cytosolic fractions of the temporal cortex of AD and control brains [165]. In AD, increased levels of Bcl-2α, Bcl-xβ, Bak Bcl-xL, and Bad have been identified in the membranous fraction, while Bcl-xβ levels increase in the cytosolic fraction. However, the levels of Bcl-xL, Bax, Bad, Bak, and ICH-1 L did not change. CPP32 was not found in either the AD or control brains. These findings indicate that cell death-regulating proteins play different roles in AD and that Bak, Bad, Bcl-2, and Bcl-x are upregulated in AD [166].

Fig. 4

Apoptosis pathways: the death receptor-mediated (extrinsic) pathway and the mitochondria-dependent (intrinsic) pathway. In the death receptor-mediated pathway, specific death receptors (e.g., Fas and the TRAIL receptors DR4 and DR5) bind to ligands, initiating a cascade that recruits procaspase 8, leading to caspase 8 activation. This pathway ultimately activates caspase 3, resulting in typical apoptotic features. The mitochondria-dependent pathway activates apoptosis by directly activating caspase 3 or cleaving bid, causing mitochondrial dysfunction, cytochrome C release, and activation of caspases 9 and 3. The balance between proapoptotic (e.g., bax, bak, and bid) and antiapoptotic (e.g., bcl-2 and bcl-XL) proteins on the mitochondrial membrane plays a critical role. These pathways culminate in cell apoptosis.

Apoptosis is initiated through two primary pathways: the extrinsic pathway, involving the binding of extracellular death ligands (such as TNF-α, TRAIL, and FASL) to death receptors; and the intrinsic pathway, characterized by mitochondrial membrane depolarization due to cellular injury. Both pathways involve a group of proteolytic enzymes known as caspases, including initiator caspases (caspase 8, caspase 9, and caspase 10) and effector caspases (caspase 3, caspase 6, and caspase 7) [167, 168]. Effector caspases cause cytomorphological and functional changes associated with apoptosis, while chromatin fragmentation results from the activation of caspase-activated deoxyribonuclease (CAD) and degradation of its inhibitor ICAD, which keeps CAD in an inactive complex [169].

In the intrinsic apoptosis pathway, mitochondria play a pivotal role in events such as mitochondrial outer membrane permeabilization, mediated by the proapoptotic proteins BAX and BAD from the Bcl-2 family. Changes in mitochondrial inner membrane permeability and transmembrane potential loss are also crucial in this process [169]. These membrane changes cause mitochondria to release cytochrome c, Smac/DIABLO, endoG, AIF, and Smac/DIABLO, resulting in the activation of effector caspases and apoptotic death. The initiator caspase 8 is triggered in the extrinsic pathway and can subsequently activate executioner caspases, i.e., caspase 3, leading to apoptotic death. Caspase 8 also acts on BID, forming the truncated BID, which may then initiate the intrinsic apoptotic cascade [165].

Identifying new biomarkers for apoptosis in AD is essential for several reasons. These biomarkers can validate previous findings on apoptosis in AD brains and evaluate the effects of therapeutic interventions. Furthermore, a combination of different biomarkers, such as apoptosis, Aβ, and tau, along with other diagnostic methods like mini-mental status examination and imaging techniques, could be beneficial for early AD detection [170]. Apoptosis biomarkers, released from dying and disassembled neurons, directly reflect the brain’s condition. Even if only a small number of cells die at any given time during the disease, it should be feasible to detect released molecules through techniques such as ELISA, mass spectrometry, and nuclear magnetic resonance spectroscopy. Alternatively, investigating peripheral blood cells, reflecting the brain’s situation, offers another avenue for addressing this issue. Changes in cellular sensitivity to apoptotic stimuli and altered expression of apoptosis-related proteins have been observed in AD blood cells, suggesting that these proteins could be potential biomarkers. The development of apoptosis-specific probes for in vivo functional brain imaging is another intriguing approach to studying neuronal death during disease progression.

CONCLUSION AND FUTURE PROSPECTS

The protein composition of the brain undergoes significant changes with age, leading to neuroinflammation, increased neuronal vulnerability, aggregation of misfolded proteins, and impairment of protein clearance pathways. These alterations in proteins play a crucial role in the development of neurodegenerative disorders. Common neurodegenerative disorders prevalent in the elderly population, such as AD, PD, and amyotrophic lateral sclerosis, have been linked to indicators of brain aging. This association implies that neurodegeneration might accelerate the aging process in the brain.

Understanding the intricate and interconnected aspects of brain aging is essential. In-depth exploration of the diverse molecular changes occurring in aging brains is necessary for the development of future therapeutic strategies aimed at enhancing cognitive health in the elderly. Prioritizing early diagnosis and interventions, with a focus on protein clearance pathways and neuroinflammation, should be a key consideration in future therapeutic approaches. Promising biomarkers, including Aβ, tau protein, and CSF, hold great potential for developing specialized therapies and assessing patient outcomes. In the future, the early diagnosis of AD can benefit from a combination of diagnostic procedures, such as neuroimaging approaches and cross-examination with biomarkers like apoptosis, Aβ, and tau.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

The authors have no funding to report.

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

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