A Detailed Analysis Of Alzheimer's Disease Pathophysiology: The Influence Of Oxidative Stress On Amyloid Precursor Protein Metabolism And Secretase Activity

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cognitive decline, memory impairment, and distinct neuropathological features such as amyloid-beta (A?) plaques and neurofibrillary tangles. Despite extensive research, the molecular mechanisms underlying AD remain incompletely understood, posing challenges for therapeutic intervention. This review delves into the intricate processes of amyloid precursor protein (APP) processing, focusing on the roles of ?-, ?-, and ?-secretases in the generation of neurotoxic A? peptides. We explore the genetic and molecular insights into APP, emphasizing the significance of secretase-mediated cleavage and its regulation by oxidative stress, cholesterol, and mitochondrial dysfunction. The interaction between these pathological pathways offers a broader understanding of AD progression, highlighting potential targets for therapeutic strategies aimed at modulating APP processing and reducing A? burden.

Keywords

Introduction

Alzheimer's disease (AD) was first identified in 1906 by the German psychiatrist Alois Alzheimer, who initially referred to it as "presenile dementia" [1,2]. Alzheimer began studying a patient named Auguste D. in 1901, who exhibited a progressive decline in cognitive abilities, including memory loss and unpredictable behaviour [3, 4]. After Auguste D.'s death in April 1906, Alzheimer conducted a postmortem analysis of her brain using histological techniques [5]. He noted the presence of numerous small "miliary foci" in the brain's cortex, which he described as resulting from the accumulation of an unusual material [6]. Alzheimer also observed what he referred to as "very peculiar changes in the neurofibrils" [7]. These findings, now recognized as senile plaques and neurofibrillary tangles, respectively, were key to understanding the disease [8]. The term "Alzheimer's disease" was later coined by Emil Kraepelin, a colleague of Alzheimer, to describe this form of presenile dementia [9,10]. Over a century later, the pathological processes initially observed by Alzheimer—amyloid-beta plaques and tau protein tangles—remain central to the study of the disease [11]. Alzheimer's disease (AD), a neurodegenerative condition identified over a century ago, remains a formidable challenge in terms of developing effective treatments [12]. Despite extensive research efforts, no cure has been achieved. As of 2021, AD affected 6.2 million individuals aged 65 and older in the United States, with projections suggesting that this number will rise to 13.8 million by 2060 [13, 14]. The increasing prevalence of AD places substantial strain on the healthcare system and on the families of those affected. Additionally, the COVID-19 pandemic has exacerbated outcomes for AD patients, accelerating progression towards death [15, 16]. Clinically, AD is characterized by cognitive decline and memory loss, with the presence of extracellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs) serving as key pathological markers [17, 18, 19]. Current hypotheses regarding the mechanisms of AD include the amyloid cascade, tau protein dysfunction, neuroinflammation, metal ion dysregulation, and oxidative stress [20, 21]. While these pathways may appear distinct, oxidative stress is a central connecting factor among them. Increased oxidative stress in the brains of AD patients is closely linked to various pathological features and is driven by several factors: the imbalance of transition metal homeostasis and its interaction with amyloid-beta (A?), the overactivation of oxidases such as NADPH oxidase and monoamine oxidase B (MAO-B), and mitochondrial dysfunction [22, 23, 24].

Research has shown that A? itself can elevate reactive oxygen species (ROS) levels, contributing to oxidative stress [25]. The methionine-35 residue on A? is particularly important for ROS generation [26]. A? oligomers have been found to directly increase ROS production by activating NADPH oxidase and indirectly influence N-methyl-D-aspartic acid receptor (NMDAR) activity, which plays a role in synaptic plasticity [27, 28]. Furthermore, metal-A? complexes, such as Cu(I/II)-A? and Fe(II/III)-A?, can produce ROS through Fenton and Fenton-like reactions, a phenomenon supported by numerous in vitro studies [29, 30]. Oxidative stress not only damages cells but also impairs mitochondrial function, leading to reduced numbers of functional mitochondria in AD patients. This mitochondrial dysfunction is associated with the loss or impairment of specific electron transport chain (ETC) enzymes, which in turn exacerbates ROS accumulation and oxidative stress [31, 32].

Neuropathological changes in Alzheimer’s disease

Genetic and Molecular Insights into Amyloid Precursor Protein in Alzheimer's Disease

The human amyloid precursor protein (APP) was first identified in 1987 by multiple research groups [33]. The gene encoding APP was subsequently mapped to chromosome 21 [34]. This gene is composed of 19 exons and spans over 170 kilobases. Alternative splicing of exons 1-13, 13a, and 14-18 produces several isoforms of APP, with APP695, APP751, and APP770 being the most predominant [35, 36]. APP is a type I transmembrane protein that is synthesized in the endoplasmic reticulum and transported through the Golgi apparatus to the trans-Golgi network (TGN), where it accumulates at higher concentrations under steady-state conditions [37, 38]. Over 32 distinct missense mutations in the APP gene have been identified across 85 families, accounting for approximately 10% to 15% of early-onset familial Alzheimer's disease (AD) [39]. These mutations typically lead to disease onset in individuals in their mid-40s to 50s [40]. It has also been observed that individuals with Down syndrome (trisomy 21) develop amyloid deposits in their 40s, leading to the neuropathological features characteristic of AD [41]. In AD patients, three morphological subtypes of amyloid deposits have been identified: diffuse deposits, where A? peptide does not aggregate into amyloid; primitive deposits, where A? aggregates into amyloid and is associated with dystrophic neurites and helical filaments; and classic deposits, where A? is highly aggregated to form a central amyloid core surrounded by a ring of dystrophic neurites [42, 43, 44]. Studies have shown that patients with familial forms of AD exhibit larger average cluster sizes of diffuse deposits compared to those with sporadic forms of the disease. There is evidence suggesting that postmenopausal estrogen replacement therapy may help prevent or delay the onset of AD. The beneficial effects of estrogen are believed to be due to the accelerated trafficking of beta-APP through the TGN, which reduces the production of beta-amyloid [45, 46]. APP can be processed at different cleavage sites by various proteases to produce peptides with biological functions [47]. Specifically, APP undergoes posttranslational proteolytic processing by ?-, ?-, and ?-secretases. Cleavage by ?-secretase results in the generation of soluble APP, while ?- and ?-secretases produce APP components with amyloidogenic properties [48].

Changes of ?-Secretase in Amyloid Precursor Protein Processing

The processing of amyloid precursor protein (APP) by ?-secretase is a critical mechanism that prevents the formation of ?-amyloid peptides, which are implicated in Alzheimer's disease [49]. APP is transported to the plasma membrane by the cytoskeletal system, where it undergoes cleavage by ?-secretase [50]. This cleavage releases a soluble fragment known as sAPP?, which plays a key role in neuronal plasticity, survival, and protection against excitotoxicity [51, 52]. Additionally, sAPP? regulates neural stem cell proliferation and is crucial for early central nervous system (CNS) development [53]. ?- Secretase itself is a type I transmembrane zinc metalloproteinase. The ?-secretase activity is primarily attributed to proteins from the ADAM family, including ADAM9, ADAM10, and ADAM17, with ADAM10 being the main enzyme responsible for this function [54, 55]. Disruption of ADAM10 activity has been shown to reduce levels of the non-amyloidogenic soluble APP, suggesting that maintaining ADAM10 function could be protective in Alzheimer's disease by promoting the ?-secretase pathway [56, 57]. ADAM10 targets several biologically significant substrates, including epidermal growth factor (EGF), betacellulin, Notch, and APP [58, 59]. Two mutations in the ADAM10 gene, associated with late-onset familial Alzheimer's disease, have been identified, and ADAM10's ?-secretase activity has been found to mediate the effects of cholesterol on APP metabolism, influenced by apolipoprotein E [60, 61]. Studies have shown that reducing cholesterol levels in various human cell lines, either through cholesterol-extracting agents or HMG-CoA reductase inhibitors, significantly increases the secretion of alpha-secretase-cleaved soluble APP [62, 63]. This suggests that cholesterol reduction promotes the non-amyloidogenic ?-secretase pathway, enhancing the production of neuroprotective soluble APP through multiple mechanisms [64, 65].

Changes of ?-Secretase in Amyloid Precursor Protein Processing

When ?-secretase cleavage of amyloid precursor protein (APP) is absent, APP molecules are internalized into endocytic compartments where they undergo cleavage by ?- and ?-secretases, leading to the generation of amyloid-beta (A?) [66, 67]. The enzyme ?-secretase 1 (BACE1), a membrane-bound aspartyl protease, plays a key role in APP metabolism [68]. BACE1 is characterized by a type I transmembrane domain near its C-terminus and is encoded by a gene located on chromosome 11, consisting of nine exons that produce a protein of 501 amino acids [69, 70, 71]. Alternative splicing of BACE1 pre-mRNA in exons 3 and 4 results in four different variants, with the full-length 501 amino acid form being the most active in cleaving APP [72]. The precursor of BACE1, known as pro-BACE1, undergoes glycosylation, phosphorylation, and cleavage by a furin-like endoprotease to become the mature BACE1 enzyme [73, 74]. After synthesis in the endoplasmic reticulum, BACE1 is transported through the secretory pathway to the plasma membrane and then re-internalized into endosomal compartments, where the acidic environment optimizes its activity [75, 76]. BACE1 expression increases with age and is notably elevated in the brain cortex of Alzheimer's disease (AD) patients [77]. This age-dependent increase in BACE1 expression may be due to defects in BACE trafficking, such as caspase-mediated degradation of the GGA protein that controls BACE intracellular sorting, or loss of regulation in BACE mRNA translation [78, 79]. Additionally, conditions such as oxidative stress, hypoxia, ischemia, and energy deprivation have been shown to elevate BACE1 expression in cellular models [80, 81]. Despite the fact that BACE1 is recognized as a key drug target for Alzheimer's disease treatment, it also cleaves several other important proteins, such as the low-density lipoprotein receptor-related protein, P-selectin glycoprotein ligand-1, neuregulin (Nrg1-type III ?1, and Nrg3), and the ?2 subunit of the voltage-gated sodium channel (Nav1, ?2), all of which play crucial roles in brain development and function [82, 83, 84].

Another ?-secretase, BACE2, can cleave APP near the ?-secretase site more efficiently than BACE1, suggesting that BACE1 is the primary ?-secretase involved in A? production [85, 86]. After cleavage of APP by BACE1, a soluble peptide called sAPP? is released. This peptide differs from sAPP? by the absence of the first 16 amino acids of the carboxyl terminus [87, 88]. The functions of sAPP? and sAPP? are notably different, with sAPP? acting as a ligand for death receptor 6, mediating axonal pruning and neuronal cell death [89, 90].

Following the ?- and ?-secretase cleavage of APP, the remaining carboxyl terminal fragments (CTFs), termed ?CFT and ?CFT, stay associated with the membrane and are subsequently cleaved by ?-secretase [91]. The overproduction of ?CFT is cytotoxic and contributes to neuronal degeneration, potentially through the generation of cytotoxic peptides such as C31 and Jcasp, which arise from the cleavage of ?CFT by ?-secretase or caspase, including the APP intracellular domain [92, 93].

Changes of ?-secretase in Amyloid Precursor Protein Processing

?-C-terminal fragment (?CFT) undergoes processing by ?-secretase to produce the p83 peptide, which is rapidly degraded, and its function remains uncharacterized [94]. ?-C-terminal fragment (?CFT) is cleaved by ?-secretase into amyloid-beta (A?) peptides, specifically A?40 and A?42 [95, 96]. Additionally, recent research has identified other cleavage sites for ?-secretase, including the ?-site, resulting in A?46, and the ?-site, yielding A?49. The ?CFT is sequentially processed at the ?-site, ?-site, and finally at the ?-site [97, 98, 99].

?-secretase is a large multiprotein complex consisting of several key components, primarily four proteins: presenilin (either PS1 or PS2), nicastrin, anterior pharynx-defective-1 (APH-1), and presenilin enhancer-2 (PEN-2) [100, 101]. This complex is located in the endoplasmic reticulum, Golgi complex, trans-Golgi network, as well as in endocytic and intermediate compartments [102].

In humans, two presenilin homologs have been identified—presenilin 1 and presenilin 2. Mutations in PS1, and occasionally PS2, have been associated with familial forms of Alzheimer’s disease (AD) [103, 104]. Over 1,000 point mutations in presenilins have been implicated in the majority of familial AD cases.

Intracellular Trafficking and Post-Translational Modifications of Amyloid Precursor Protein

Amyloid precursor protein (APP) is synthesized in the endoplasmic reticulum and transported anterogradely to the Golgi apparatus, eventually reaching the trans-Golgi network (TGN) in specialized vesicles via conventional kinesin [105, 106]. Within the TGN, APP undergoes various post-translational modifications, including phosphorylation, tyrosine sulfation, and N- and O-glycosylation [107]. Recent studies have shown that calsyntenin-1 co-transports with APP along axons, and its levels in the brain are reduced in individuals with Alzheimer’s disease, with this reduction correlating with increased amyloid-beta (A?) levels [108, 109]. The transport of APP vesicles also requires the GTPase activity of Rab3, a small G-protein involved in the late stages of exocytosis. Upon insertion at the plasma membrane, APP is rapidly internalized through clathrin-mediated endocytosis, with the C-terminal sequence YENPY serving as the primary signal for this process [110]. Several intracellular adaptors, such as Fe65, Mint proteins, Dab1, and JIP, interact with the C-terminal region of APP. Additionally, lipoprotein receptor-related protein 1 (LRP1) and apolipoprotein E receptor 2 can directly interact with APP, either intracellularly through adaptors like Dab1, Mint1, or Fe65, or extracellularly via F-spondin [111, 112]. After internalization, APP can follow various pathways. It may be rapidly transported from the cell surface to lysosomes for degradation or be processed in the proteasome. Alternatively, APP can be transported from endosomes back to the Golgi apparatus and/or TGN, from where it may be redistributed to the plasma membrane [113].

Role of Amyloid Precursor Protein and Amyloid-Beta in Synaptic Function and Neurodegeneration

The extracellular domain of amyloid precursor protein (APP) plays a crucial role in promoting synapse formation, with trans-synaptic interactions between pre- and postsynaptic APP contributing to synaptic adhesion [114, 115]. Studies using APP and BACE1 knock-out mice have shown impaired memory, suggesting that amyloid-beta (A?) is essential for learning and memory processes [116]. Recent findings indicate that low levels of A? can enhance hippocampal long-term potentiation and memory, revealing a novel positive modulatory role for A? in neurotransmission and cognitive function. Picomolar concentrations of A?, present in both cerebrospinal fluid and plasma of healthy individuals, have been shown to significantly increase long-term potentiation, whereas higher nanomolar concentrations are associated with reduced potentiation in the hippocampus [117, 118]. There are two primary toxic species of A?: A?40 and A?42. An increased A?42/A?40 ratio is characteristic of Alzheimer's disease (AD) patients. Most A? is secreted as A?40, while A?42, although produced in smaller quantities, is the main amyloid peptide responsible for forming amyloid fibrils in AD [119]. A?42 tends to self-associate into dimers, soluble oligomers, and eventually insoluble fibrillar aggregates [120]. Extracellular A? can be internalized by cells for intracellular degradation, often involving enzymes like insulin-degrading enzyme and neprilysin [121]. This process suggests a mechanism for amyloid plaque formation, where initially soluble extracellular A? becomes internalized, sorted into multivesicular bodies, and ultimately disrupts cellular function, leading to cell death and the release of amyloid species into the extracellular space [122]. Additionally, cytotoxic effects of A? may also be mediated by peptides like C31 and Jcasp, which are released during ?C-terminal fragment cleavage. Over 30 studies have evaluated plasma levels of A?40 and A?42 as diagnostic markers or biological risk factors. Elevated A?42 and A?42/A?40 ratios have been observed in unaffected carriers of familial AD mutations compared to non-carriers [123]. However, in mutation carriers with early-stage AD (characterized by a Clinical Dementia Rating of 0.5), A?42 levels were lower, supporting the hypothesis that A?42 levels decline before the onset of overt disease [124]. Recent research has also documented the transfer of A? between neurons, which depends on synaptic connections. This transfer may help explain the propagation of neurodegenerative pathology across anatomically connected brain regions [125, 126]. The degeneration of the entorhinal cortex, observed in the early stages of AD, and the subsequent degeneration of connected areas may be linked to the spread of A?, as demonstrated by the exogenous injection of A? aggregates from AD patient brain extracts into APP transgenic mice, which induced cerebral amyloidogenesis that progressed from the injection site [127, 128, 129].

Role of Tau Protein in Microtubule Stability and Neurodegeneration

The human tau protein gene (MAPT) is located on chromosome 17 and consists of 15 exons, with exons 2, 3, and 10 undergoing alternative splicing, resulting in six different isoforms [130, 131]. The longest tau isoform contains 79 potential serine and threonine residues that can be phosphorylated, with more than 30 sites typically phosphorylated [132]. Tau protein plays a crucial role in stabilizing microtubules within neurons, promoting neurite outgrowth, facilitating membrane interactions, anchoring enzymes, and aiding in the axonal transport of organelles to nerve terminals [133, 134]. Phosphorylation of tau regulates its binding to and assembly with microtubules [135]. In Alzheimer's disease (AD), tau becomes hyperphosphorylated, leading to its accumulation in neurons and the formation of paired helical filaments [136]. This hyperphosphorylated tau loses its ability to bind microtubules, resulting in microtubule destabilization and subsequent neurodegeneration [137]. Astrocytes are essential in mediating A?-induced tau phosphorylation in primary neurons. Although the exact factors causing tau hyperphosphorylation are not fully understood, it is believed that multiple factors are involved [138, 139]. The abnormal binding of hyperphosphorylated tau to microtubules, characteristic of AD, causes microtubule instability, disrupting axonal transport, which is essential for the movement of organelles such as mitochondria and A? along microtubules [140]. Disrupted axonal transport can lead to the accumulation of amyloid precursor protein (APP) in the cell body, which has been linked to increased oxidative stress due to impaired mitochondrial transport.

No mutations in the tau gene have been directly linked to AD; however, the H1c subhaplotype of the MAPT gene has been associated with an increased risk of AD in certain populations. Specifically, the rs242557 polymorphism, part of the H1c subhaplotype, has been shown to increase MAPT gene expression . Additionally, the interaction between the H1/H2 MAPT haplotype and functional SNPs in the GSK3B gene may influence AD risk [141, 142, 143]. Recent studies have highlighted the relationship between tau protein and mitochondria. Tau has been found on mitochondrial membranes, and proper mitochondrial trafficking and distribution in neurons are critical for neuronal function, particularly in meeting energy and Ca2+ buffering needs at synapses [144]. Mitochondria rapidly move within axons and dendrites, with synaptic activity influencing their motility, morphology, and localization [145] In neurons overexpressing tau protein, mitochondria were observed to disappear from neurites and concentrate in the cell body. This redistribution is thought to be due to the inhibition of plus-end-directed transport (away from the cell center) by kinesin motors, leading to a dominance of minus-end-directed transport (toward the cell center) by dynein-like motors [146].

Role of Apolipoprotein E and Cholesterol in Alzheimer's Disease

Apolipoprotein E (ApoE) is a cholesterol transport protein that primarily exists within lipoprotein complexes, along with other apolipoproteins and proteins, in plasma and cerebrospinal fluid (CSF) [147, 148]. In humans, three ApoE alleles have been identified—?2 (Cys112/Cys158), ?3 (Cys112/Arg158), and ?4 (Arg112/Arg158)—based on variations at two polymorphic sites. These amino acid differences are significant as they impact the charge and structural properties of the protein [149, 150]. The ApoE gene has been widely studied in relation to both familial late-onset and sporadic late-onset Alzheimer’s disease (AD). Among these, the ApoE4 allele is the most strongly associated with increased genetic risk for AD. The presence of one ?4 allele increases the risk of cognitive impairment and late-onset AD by 2- to 3-fold, while two copies of the allele raise this risk by 5- to 10-fold [151]. Similar risk levels have been observed for the progression from cognitive impairment to dementia. ApoE4 carriers also tend to have higher total and LDL cholesterol levels, which have been linked to increased production of amyloid-beta (A?), a key factor in AD pathology [152, 153]. High cholesterol levels are implicated in the overproduction of A?, with some evidence suggesting that A? may have a physiological role in regulating cholesterol transport [154]. In individuals aged 50 and older, statin use has been associated with a significantly reduced risk of developing dementia, independent of hyperlipidemia or exposure to non-statin lipid-lowering agents. Additionally, cholesterol-rich environments have been shown to decrease the levels of soluble amyloid precursor protein alpha (sAPP?), as ADAM10, an enzyme responsible for cleaving APP, is less effective in such conditions. Changes in cellular cholesterol levels in AD may therefore contribute to neuronal degeneration by reducing sAPP? production [155, 156].

Vascular and Mitochondrial Contributions to Alzheimer's Disease Pathogenesis

The pathogenesis of Alzheimer’s disease (AD) has been linked to both vascular and mitochondrial dysfunction [157]. Several vascular risk factors, such as diabetes mellitus, hypertension, atherosclerosis, hypercholesterolemia, metabolic syndrome, and obesity, have been associated with an increased risk of AD [158, 159]. The apolipoprotein E (ApoE) genotype, which influences cholesterol transport, is also implicated as a vascular risk factor in AD. Patients with AD frequently exhibit cerebrovascular pathologies, including cerebral microbleeding and microinfarcts [160]. Microinfarcts are more common in individuals with vascular dementia, AD, or mixed dementia compared to non-demented older adults. Cerebral hypoperfusion may trigger or exacerbate neurodegenerative processes, leading to amyloid deposition, synaptic dysfunction, and cognitive decline. The ApoE4 allele is strongly associated with increased amyloid-beta (A?) deposition in the capillary walls, further contributing to the vascular component of AD [161, 162]. Additionally, oxidative stress, which can be exacerbated by hypoxia and mitochondrial dysfunction, plays a significant role in AD pathogenesis [163]. Mitochondrial dysfunction in AD may arise from abnormalities in mitochondrial metabolism, biogenesis, axonal transport, fusion and fission processes, and autophagy [164]. Functional mitochondria are delivered to synaptic terminals via anterograde transport by kinesin, while dysfunctional mitochondria are returned to the cell soma by dynein [165]. Hyperphosphorylation of tau protein impairs mitochondrial transport, leading to energy deficits at synaptic terminals and subsequent synaptic damage. The accumulation of amyloid precursor protein (APP) within mitochondria disrupts their function and impairs brain energy metabolism. Moreover, interactions between A? and the NH2-tau fragment have been shown to inhibit the mitochondrial adenine nucleotide translocator-1 (ANT-1), which is crucial for exporting ATP from mitochondria to the cytosol and plays a role in regulating the intrinsic apoptosis pathway [166, 167].

CONCLUSION

This review elucidates the multifaceted relationship between oxidative stress, amyloid precursor protein (APP) processing, and Alzheimer's disease (AD) pathophysiology, highlighting the critical roles of ?-, ?-, and ?-secretases. It is evident that the dysregulation of APP processing, influenced by oxidative stress and other factors such as cholesterol metabolism and mitochondrial dysfunction, plays a pivotal role in AD progression. The intricate interplay between these secretases determines the balance between neuroprotective and neurotoxic outcomes, with oxidative stress exacerbating the production of amyloid-beta (A?) peptides, a hallmark of AD. Moreover, the review underscores the potential therapeutic implications of targeting secretase activity and modulating oxidative stress. Strategies aimed at enhancing ?-secretase activity, reducing ?- and ?-secretase-mediated A? production, and mitigating oxidative stress could offer promising avenues for slowing or preventing AD progression. Understanding these mechanisms provides a comprehensive framework for developing targeted interventions that address the underlying causes of AD, offering hope for more effective treatments in the future.

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