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.

REFERENCES

1. Lage JM. 100 Years of Alzheimer's disease (1906–2006). Journal of Alzheimer's Disease. 2006 Jan 1;9(s3):15-26.
2. Tonkonogy J, Moak GS. Alois Alzheimer on presenile dementia. Journal of geriatric psychiatry and neurology. 1988 Oct;1(4):199-206.
3. Emilien G, Durlach C, Minaker KL, Winblad B, Gauthier S, Maloteaux JM, Emilien G, Durlach C, Minaker KL, Winblad B, Gauthier S. Alzheimer disease. Alzheimer Disease: Neuropsychology and Pharmacology. 2004:3-17.
4. Hodges JR. Alzheimer's centennial legacy: origins, landmarks and the current status of knowledge concerning cognitive aspects. Brain. 2006 Nov 1;129(11):2811-22.
5. Graeber MB, Kösel S, Grasbon-Frodl E, Möller HJ, Mehraein P. Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D. Neurogenetics. 1998 Mar;1:223-8.
6. Bot JC, Mazzai L, Hagenbeek RE, Ingala S, Van Oosten B, Sanchez-Aliaga E, Barkhof F. Brain miliary enhancement. Neuroradiology. 2020 Mar;62(3):283-300.
7. Terry RD. The fine structure of neurofibrillary tangles in Alzheimer's disease.
8. Brion JP. Neurofibrillary tangles and Alzheimer’s disease. European neurology. 1998 Oct 14;40(3):130-40.
9. Weber MM. Aloys Alzheimer, a coworker of Emil Kraepelin. Journal of psychiatric research. 1997 Nov 1;31(6):635-43.
10. Borri M. Memory and Alzheimer's Disease. Medicina nei Secoli: Journal of History of Medicine and Medical Humanities. 2022 Oct 27;34(2):57-70.
11. Paula VD, Guimarães FM, Diniz BS, Forlenza OV. Neurobiological pathways to Alzheimer's disease: Amyloid-beta, TAU protein or both?. Dementia & neuropsychologia. 2009;3(3):188-94.
12. Rashid U, Ansari FL. Challenges in designing therapeutic agents for treating Alzheimer’s disease-From serendipity to rationality. InDrug Design and Discovery in Alzheimer's Disease 2014 Jan 1 (pp. 40-141). Elsevier.
13. Alzheimer's Association. 2019 Alzheimer's disease facts and figures. Alzheimer's & dementia. 2019 Mar;15(3):321-87.
14. Saxena K, Nettles S. Understanding Alzheimer’s Risk Factors Associated with the Prevalence of US Populations and Women. Journal of Student Research. 2022 Feb 28;11(1).
15. Brown EE, Kumar S, Rajji TK, Pollock BG, Mulsant BH. Anticipating and mitigating the impact of the COVID-19 pandemic on Alzheimer's disease and related dementias. The American Journal of Geriatric Psychiatry. 2020 Jul 1;28(7):712-21.
16. Rolland JS. COVID?19 pandemic: Applying a multisystemic lens. Family process. 2020 Sep;59(3):922-36.
17. Ferreira MJ, Soares Martins T, Alves SR, Rosa IM, Vogelgsang J, Hansen N, Wiltfang J, da Cruz e Silva OA, Vitorino R, Henriques AG. Bioinformatic analysis of the SPs and NFTs proteomes unravel putative biomarker candidates for Alzheimer's disease. Proteomics. 2023 Aug;23(15):2200515.
18. Chiba T. Emerging therapeutic strategies in Alzheimer's disease. Neurodegenerative Diseases. 2013 May 15.
19. Imhof A, Kövari E, von Gunten A, Gold G, Rivara CB, Herrmann FR, Hof PR, Bouras C, Giannakopoulos P. Morphological substrates of cognitive decline in nonagenarians and centenarians: a new paradigm?. Journal of the neurological sciences. 2007 Jun 15;257(1-2):72-9.
20. Roy RG, Mandal PK, Maroon JC. Oxidative stress occurs prior to amyloid A? plaque formation and tau phosphorylation in Alzheimer’s disease: Role of glutathione and metal ions. ACS Chemical Neuroscience. 2023 Aug 10;14(17):2944-54.
21. Huat TJ, Camats-Perna J, Newcombe EA, Valmas N, Kitazawa M, Medeiros R. Metal toxicity links to Alzheimer's disease and neuroinflammation. Journal of molecular biology. 2019 Apr 19;431(9):1843-68.
22. Angelova PR. Sources and triggers of oxidative damage in neurodegeneration. Free Radical Biology and Medicine. 2021 Sep 1;173:52-63.
23. Sbodio JI, Snyder SH, Paul BD. Redox mechanisms in neurodegeneration: from disease outcomes to therapeutic opportunities. Antioxidants & Redox Signaling. 2019 Apr 10;30(11):1450-99.
24. Butterfield DA, Favia M, Spera I, Campanella A, Lanza M, Castegna A. Metabolic features of brain function with relevance to clinical features of Alzheimer and Parkinson diseases. Molecules. 2022 Jan 30;27(3):951.
25. Bhatt S, Puli L, Patil CR. Role of reactive oxygen species in the progression of Alzheimer’s disease. Drug discovery today. 2021 Mar 1;26(3):794-803.
26. Butterfield DA, Sultana R. Methionine?35 of A? (1–42): importance for oxidative stress in Alzheimer disease. Journal of amino acids. 2011;2011(1):198430.
27. Shelat PB, Chalimoniuk M, Wang JH, Strosznajder JB, Lee JC, Sun AY, Simonyi A, Sun GY. Amyloid beta peptide and NMDA induce ROS from NADPH oxidase and AA release from cytosolic phospholipase A2 in cortical neurons. Journal of neurochemistry. 2008 Jul;106(1):45-55.
28. Simonyi A, He Y, Sheng W, Sun AY, Wood WG, Weisman GA, Sun GY. Targeting NADPH Oxidase and Phospholipases A 2 in Alzheimer’s Disease. Molecular neurobiology. 2010 Jun;41:73-86.
29. Han J, Du Z, Lim MH. Mechanistic insight into the design of chemical tools to control multiple pathogenic features in Alzheimer’s disease. Accounts of Chemical Research. 2021 Oct 4;54(20):3930-40
30. Savelieff MG, DeToma AS, Derrick JS, Lim MH. The ongoing search for small molecules to study metal-associated amyloid-? species in Alzheimer’s disease. Accounts of chemical research. 2014 Aug 19;47(8):2475-82.
31. Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2014 Aug 1;1842(8):1240-7.
32. Bhatia V, Sharma S. Role of mitochondrial dysfunction, oxidative stress and autophagy in progression of Alzheimer's disease. Journal of the neurological sciences. 2021 Feb 15;421:117253.
33. Arai H, Lee VM, Messinger ML, Greenberg BD, Lowery DE, Trojanowski JQ. Expression patterns of ??amyloid precursor protein (??APP) in neural and nonneural human tissues from alzheimer's disease and control subjects. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 1991 Nov;30(5):686-93.
34. Haltia M, Viitanen M, Sulkava R, Ala?Hurula V, Poyhonen M, Goldfarb L, Brown P, Levy E, Houlde H, Crook R, Goate A. Chromosome 14–encoded Alzheimer's disease: genetic and clinicopathological description. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 1994 Sep;36(3):362-7.
35. Sandbrink R, Masters CL, Beyreuther K. Similar alternative splicing of a non-homologous domain in beta A4-amyloid protein precursor-like proteins. Journal of Biological Chemistry. 1994 May 13;269(19):14227-34.
36. Ling Y, Morgan K, Kalsheker N. Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer’s disease. The international journal of biochemistry & cell biology. 2003 Nov 1;35(11):1505-35.
37. Choy RW, Cheng Z, Schekman R. Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid ? (A?) production in the trans-Golgi network. Proceedings of the National Academy of Sciences. 2012 Jul 24;109(30):E2077-82.
38. Yan R, Han P, Miao H, Greengard P, Xu H. The transmembrane domain of the Alzheimer's ?-secretase (BACE1) determines its late Golgi localization and access to ?-amyloid precursor protein (APP) substrate. Journal of Biological Chemistry. 2001 Sep 28;276(39):36788-96.
39. Cruchaga C, Chakraverty S, Mayo K, Vallania FL, Mitra RD, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, Boeve BF. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PloS one. 2012 Feb 1;7(2):e31039.
40. Head E, T Lott I, M Wilcock D, A Lemere C. Aging in Down syndrome and the development of Alzheimer’s disease neuropathology. Current Alzheimer Research. 2016 Jan 1;13(1):18-29.
41. Doran E, Keator D, Head E, Phelan MJ, Kim R, Totoiu M, Barrio JR, Small GW, Potkin SG, Lott IT. Down syndrome, partial trisomy 21, and absence of Alzheimer’s disease: the role of APP. Journal of Alzheimer's Disease. 2017 Jan 1;56(2):459-70.
42. Walker LC. A? plaques. Free neuropathology. 2020 Jan;1.
43. Armstrong RA. ?-amyloid plaques: stages in life history or independent origin?. Dementia and geriatric cognitive disorders. 1998 Jun 19;9(4):227-38.
44. Jankovska N, Olejar T, Matej R. Extracellular amyloid deposits in Alzheimer’s and Creutzfeldt–Jakob disease: Similar behavior of different proteins?. International Journal of Molecular Sciences. 2020 Dec 22;22(1):7.
45. Gandy S, Petanceska S. Regulation of Alzheimer ?-amyloid precursor trafficking and metabolism. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2000 Jul 26;1502(1):44-52.
46. Gandy S, Petanceska S. Regulation of Alzheimer ß-amyloid precursor trafficking and metabolism. Neuropathology and Genetics of Dementia. 2001:85-100.
47. Ling Y, Morgan K, Kalsheker N. Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer’s disease. The international journal of biochemistry & cell biology. 2003 Nov 1;35(11):1505-35.
48. Ling Y, Morgan K, Kalsheker N. Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer’s disease. The international journal of biochemistry & cell biology. 2003 Nov 1;35(11):1505-35.
49. Zhang H, Ma Q, Zhang YW, Xu H. Proteolytic processing of Alzheimer’s ??amyloid precursor protein. Journal of Neurochemistry: REVIEW. 2012 Jan;120:9-21.
50. Vincent B, Checler F. ?-Secretase in Alzheimer's disease and beyond: mechanistic, regulation and function in the shedding of membrane proteins. Current Alzheimer Research. 2012 Feb 1;9(2):140-56.
51. Zhang YW, Thompson R, Zhang H, Xu H. APP processing in Alzheimer's disease. Molecular brain. 2011 Dec;4:1-3.
52. Nhan HS, Chiang K, Koo EH. The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. Acta neuropathologica. 2015 Jan;129:1-9.
53. Coronel R, Bernabeu-Zornoza A, Palmer C, Muñiz-Moreno M, Zambrano A, Cano E, Liste I. Role of amyloid precursor protein (APP) and its derivatives in the biology and cell fate specification of neural stem cells. Molecular neurobiology. 2018 Sep;55:7107-17.
54. Saftig P, Lichtenthaler SF. The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain. Progress in neurobiology. 2015 Dec 1;135:1-20.
55. Wetzel S, Seipold L, Saftig P. The metalloproteinase ADAM10: A useful therapeutic target?. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2017 Nov 1;1864(11):2071-81.
56. Peron R, Vatanabe IP, Manzine PR, Camins A, Cominetti MR. Alpha-secretase ADAM10 regulation: insights into Alzheimer’s disease treatment. Pharmaceuticals. 2018 Jan 29;11(1):12.
57. Saftig P, Lichtenthaler SF. The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain. Progress in neurobiology. 2015 Dec 1;135:1-20.
58. Musardo S, Marcello E. Synaptic dysfunction in Alzheimer's disease: From the role of amyloid ?-peptide to the ?-secretase ADAM10. European journal of pharmacology. 2017 Dec 15;817:30-7.
59. Qin W, Ho L, Wang J, Peskind E, Pasinetti GM. S100A7, a novel Alzheimer's disease biomarker with non-amyloidogenic ?-secretase activity acts via selective promotion of ADAM-10. PLoS One. 2009 Jan 13;4(1):e4183.
60. de Oliveira SD, Alexandre-Silva V, Popolin CP, de Sousa DB, Grigoli MM, de Carvalho Pelegrini LN, Manzine PR, Espuny AC, Marcello E, Endres K, Cominetti MR. ADAM10 isoforms: optimizing usage of antibodies based on protein regulation, structural features, biological activity and clinical relevance to Alzheimer’s disease. Ageing Research Reviews. 2024 Aug 21:102464.
61. Azizi H. Effects of DHA and EGCG on the alpha-secretase mediated processing of APP (Doctoral dissertation, University of Guelph).
62. Šerý O, Povová J, Míšek I, Pešák L, Janout V. Molecular mechanisms of neuropathological changes in Alzheimer’s disease: a review. Folia neuropathologica. 2013;51(1):1-9.
63. Kojro E, Postina R. Regulated Proteolysis of RAGE and A?PP as Possible Link Between Type 2 Diabetes Mellitus and Alzheimer's Disease. Journal of Alzheimer's Disease. 2009 Jan 1;16(4):865-78.
64. Rojas?Fernandez CH, Chen M, Fernandez HL. Implications of Amyloid Precursor Protein and Subsequent ??Amyloid Production to the Pharmacotherapy of Alzheimer's Disease. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2002 Dec;22(12):1547-63.
65. Obregon D, Hou H, Deng J, Giunta B, Tian J, Darlington D, Shahaduzzaman M, Zhu Y, Mori T, Mattson MP, Tan J. Soluble amyloid precursor protein-? modulates ?-secretase activity and amyloid-? generation. Nature communications. 2012 Jan;3(1):777.
66. Marks N, Berg MJ. BACE and ?-secretase characterization and their sorting as therapeutic targets to reduce amyloidogenesis. Neurochemical research. 2010 Feb;35:181-210.
67. Hur JY. ?-Secretase in Alzheimer’s disease. Experimental & molecular medicine. 2022 Apr;54(4):433-46.
68. Haass C, Kaether C, Thinakaran G, Sisodia S. Trafficking and proteolytic processing of APP. Cold Spring Harbor perspectives in medicine. 2012 May 1;2(5):a006270.
69. Penzkofer S. Screen for kinases affecting amyloidogenic cleavage by BACE1.
70. Ugbaja SC, Lawal MM, Kumalo HM. An Overview of ?-Amyloid Cleaving Enzyme 1 (BACE1) in Alzheimer's Disease Therapy: Elucidating its Exosite-Binding Antibody and Allosteric Inhibitor. Current Medicinal Chemistry. 2022 Jan 1;29(1):114-35.
71. C Kandalepas P, Vassar R. The normal and pathologic roles of the Alzheimer's ?-secretase, BACE1. Current Alzheimer Research. 2014 Jun 1;11(5):441-9.
72. Mowrer KR, Wolfe MS. Promotion of BACE1 mRNA alternative splicing reduces amyloid ?-peptide production. Journal of Biological Chemistry. 2008 Jul 4;283(27):18694-701.
73. Yan R, Han P, Miao H, Greengard P, Xu H. The transmembrane domain of the Alzheimer's ?-secretase (BACE1) determines its late Golgi localization and access to ?-amyloid precursor protein (APP) substrate. Journal of Biological Chemistry. 2001 Sep 28;276(39):36788-96.
74. Jiang S, Wang Y, Ma Q, Zhou A, Zhang X, Zhang YW. M1 muscarinic acetylcholine receptor interacts with BACE1 and regulates its proteosomal degradation. Neuroscience letters. 2012 May 2;515(2):125-30.
75. Vandendriessche C, Bruggeman A, Van Cauwenberghe C, Vandenbroucke RE. Extracellular vesicles in Alzheimer’s and Parkinson’s disease: small entities with large consequences. Cells. 2020 Nov 15;9(11):2485.
76. Galán-Acosta L. Recombinant Brichos Domains Delivered over the Blood-Brain Barrier: A Possible Way to Treat Alzheimer´ s Disease (Doctoral dissertation, Karolinska Institutet (Sweden)).
77. Coulson DT, Beyer N, Quinn JG, Brockbank S, Hellemans J, Irvine GB, Ravid R, Johnston JA. BACE1 mRNA expression in Alzheimer's disease postmortem brain tissue. Journal of Alzheimer's Disease. 2010 Jan 1;22(4):1111-22.
78. Meur S, Mukherjee S, Roy S, Karati D. Role of PIM Kinase Inhibitor in the Treatment of Alzheimer’s Disease. Molecular Neurobiology. 2024 May 30:1-5.
79. Faltraco F, Lista S, Garaci FG, Hampel H. Epigenetic mechanisms in Alzheimer’s disease: State-of-the-art. Eur J Neurodegener Dis. 2012;1(1):1-9.
80. Daulatzai MA. Death by a thousand cuts in Alzheimer’s disease: hypoxia—the prodrome. Neurotoxicity research. 2013 Aug;24(2):216-43.
81. Moussavi Nik SH, Wilson L, Newman M, Croft K, Mori TA, Musgrave I, Lardelli M. The BACE1-PSEN-A?PP regulatory axis has an ancient role in response to low oxygen/oxidative stress. Journal of Alzheimer's Disease. 2012 Jan 1;28(3):515-30.
82. Vassar R, Cole SL. The basic biology of BACE1: A key therapeutic target for Alzheimer's disease. Current genomics. 2007 Dec 1;8(8):509-30.
83. Evin G, Hince C. BACE1 as a therapeutic target in Alzheimer’s disease: rationale and current status. Drugs & aging. 2013 Oct;30:755-64.
84. Dislich B, Lichtenthaler SF. The membrane-bound aspartyl protease BACE1: molecular and functional properties in Alzheimer’s disease and beyond. Frontiers in physiology. 2012 Feb 17;3:8.
85. Cole SL, Vassar R. The role of amyloid precursor protein processing by BACE1, the ?-secretase, in Alzheimer disease pathophysiology. Journal of Biological Chemistry. 2008 Oct 31;283(44):29621-5.
86. Willem M, Lammich S, Haass C. Function, regulation and therapeutic properties of ?-secretase (BACE1). InSeminars in cell & developmental biology 2009 Apr 1 (Vol. 20, No. 2, pp. 175-182). Academic Press.
87. Zhang YW, Thompson R, Zhang H, Xu H. APP processing in Alzheimer's disease. Molecular brain. 2011 Dec;4:1-3.
88. Del Prete D, Lombino F, Liu X, D'Adamio L. APP is cleaved by Bace1 in pre-synaptic vesicles and establishes a pre-synaptic interactome, via its intracellular domain, with molecular complexes that regulate pre-synaptic vesicles functions. PloS one. 2014 Sep 23;9(9):e108576.
89. Dar NJ, Glazner GW. Deciphering the neuroprotective and neurogenic potential of soluble amyloid precursor protein alpha (sAPP?). Cellular and Molecular Life Sciences. 2020 Jun;77:2315-30.
90. Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M. RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9.
91. Saleh O, Albakri K, Altiti A, Abutair I, Shalan S, Mohd OB, Negida A, Mushtaq G, Kamal MA. The Role of Non-coding RNAs in Alzheimer's Disease: Pathogenesis, Novel Biomarkers, and Potential Therapeutic Targets. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2024 Jun 1;23(6):731-45.
92. Hua J. Rôle des récepteurs P2X4 dans la dégradation d’ApoE: implication dans la maladie d’Alzheimer (Doctoral dissertation, Université Montpellier).
93. Chukwu LC, Ekenjoku JA, Ohadoma SC, Olisa CL, Okam PC, Okany CC, Ramalam MA, Innocent OC. Advances in the pathogenesis of Alzheimer’s disease: A re-evaluation of the Amyloid cascade hypothesis. World Journal of Advanced Research and Reviews. 2023;17(2):882-904.
94. Saleh O, Albakri K, Altiti A, Abutair I, Shalan S, Mohd OB, Negida A, Mushtaq G, Kamal MA. The Role of Non-coding RNAs in Alzheimer's Disease: Pathogenesis, Novel Biomarkers, and Potential Therapeutic Targets. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2024 Jun 1;23(6):731-45.
95. Findeis MA. The role of amyloid ? peptide 42 in Alzheimer's disease. Pharmacology & therapeutics. 2007 Nov 1;116(2):266-86.
96. Svedruži? ŽM, Šendula Jengi? V, Ostoji? L. The Binding of Different Substrate Molecules at the Docking Site and the Active Site of ?-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer’s Disease. International Journal of Molecular Sciences. 2023 Jan 17;24(3):1835.
97. Fernandez MA, Biette KM, Dolios G, Seth D, Wang R, Wolfe MS. Transmembrane substrate determinants for ?-secretase processing of APP CTF?. Biochemistry. 2016 Oct 11;55(40):5675-88.
98. Pinnix I, Ghiso JA, Pappolla MA, Sambamurti K. Major carboxyl terminal fragments generated by ?-secretase processing of the Alzheimer amyloid precursor are 50 and 51 amino acids long. The American Journal of Geriatric Psychiatry. 2013 May 1;21(5):474-83.
99. Aguayo?Ortiz R, Dominguez L. Generation of Amyloid?? Peptides by ??Secretase. Israel Journal of Chemistry. 2017 Jul;57(7-8):574-85.
100. De Strooper B. Aph-1, Pen-2, and nicastrin with presenilin generate an active ?-secretase complex. Neuron. 2003 Apr 10;38(1):9-12.
101. Cheng H, Vetrivel KS, Drisdel RC, Meckler X, Gong P, Leem JY, Li T, Carter M, Chen Y, Nguyen P, Iwatsubo T. S-palmitoylation of ?-secretase subunits nicastrin and APH-1. Journal of Biological Chemistry. 2009 Jan 16;284(3):1373-84.
102. Griffiths G, Simons K. The trans Golgi network: sorting at the exit site of the Golgi complex. Science. 1986 Oct 24;234(4775):438-43.
103. Ponting CP, Hutton M, Nyborg A, Baker M, Jansen K, Golde TE. Identification of a novel family of presenilin homologues. Human molecular genetics. 2002 May 1;11(9):1037-44.
104. Kovacs DM, Tanzi RE. Monogenic determinants of familial Alzheimer's disease: presenilin-1 mutations. Cellular and Molecular Life Sciences CMLS. 1998 Sep;54:902-9.
105. Muresan V, Muresan ZL. Amyloid-? precursor protein: multiple fragments, numerous transport routes and mechanisms. Experimental cell research. 2015 May 15;334(1):45-53.
106. Brunholz S, Sisodia S, Lorenzo A, Deyts C, Kins S, Morfini G. Axonal transport of APP and the spatial regulation of APP cleavage and function in neuronal cells. Experimental brain research. 2012 Apr;217:353-64.
107. Wang X, Zhou X, Li G, Zhang Y, Wu Y, Song W. Modifications and trafficking of APP in the pathogenesis of Alzheimer’s disease. Frontiers in molecular neuroscience. 2017 Sep 15;10:294.
108. Giedraitis V, Sundelöf J, Irizarry MC, Gårevik N, Hyman BT, Wahlund LO, Ingelsson M, Lannfelt L. The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer's disease. Neuroscience letters. 2007 Nov 19;427(3):127-31.
109. Song F, Poljak A, Valenzuela M, Mayeux R, Smythe GA, Sachdev PS. Meta-analysis of plasma amyloid-? levels in Alzheimer's disease. Journal of Alzheimer's Disease. 2011 Jan 1;26(2):365-75.
110. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of ?-amyloid. Journal of Biological Chemistry. 2001 Oct 26;276(43):40353-61.
111. Chau DD, Ng LL, Zhai Y, Lau KF. Amyloid precursor protein and its interacting proteins in neurodevelopment. Biochemical Society Transactions. 2023 Aug 31;51(4):1647-59.
112. Hoe HS, Tran TS, Matsuoka Y, Howell BW, Rebeck GW. DAB1 and Reelin effects on amyloid precursor protein and ApoE receptor 2 trafficking and processing. Journal of Biological Chemistry. 2006 Nov 17;281(46):35176-85.
113. Lippincott-Schwartz J, Yuan L, Tipper C, Amherdt M, Orci L, Klausner RD. Brefeldin A's effects on endosomes, lysosomes, and the TGN suggest a general mechanism for regulating organelle structure and membrane traffic. Cell. 1991 Nov 1;67(3):601-16.
114. Hoe HS, Lee HK, Pak DT. The upside of APP at synapses. CNS neuroscience & therapeutics. 2012 Jan;18(1):47-56.
115. Yamagata M, Sanes JR, Weiner JA. Synaptic adhesion molecules. Current opinion in cell biology. 2003 Oct 1;15(5):621-32.
116. Morley JE, Farr SA. The role of amyloid-beta in the regulation of memory. Biochemical pharmacology. 2014 Apr 15;88(4):479-85.
117. Aguzzi A, O'connor T. Protein aggregation diseases: pathogenicity and therapeutic perspectives. Nature reviews Drug discovery. 2010 Mar;9(3):237-48.
118. Ghosh AK, Brindisi M. Organic carbamates in drug design and medicinal chemistry. Journal of medicinal chemistry. 2015 Apr 9;58(7):2895-940.
119. Gu L, Guo Z. Alzheimer's A?42 and A?40 peptides form interlaced amyloid fibrils. Journal of neurochemistry. 2013 Aug;126(3):305-11.
120. Qiu T, Liu Q, Chen YX, Zhao YF, Li YM. A?42 and A?40: similarities and differences. Journal of peptide science. 2015 Jul;21(7):522-9.
121. Malito E, Hulse RE, Tang WJ. Amyloid ?-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin. Cellular and Molecular Life Sciences. 2008 Aug;65:2574-85.
122. Gouras GK, Almeida CG, Takahashi RH. Intraneuronal A? accumulation and origin of plaques in Alzheimer's disease. Neurobiology of aging. 2005 Oct 1;26(9):1235-44.
123. Thordardottir S. Biomarkers in Preclinical Familial Alzheimer Disease. Karolinska Institutet (Sweden); 2018.
124. Lin SY, Lin KJ, Lin PC, Huang CC, Chang CC, Lee YC, Hsiao IT, Yen TC, Huang WS, Yang BH, Wang PN. Plasma amyloid assay as a pre-screening tool for amyloid positron emission tomography imaging in early stage Alzheimer’s disease. Alzheimer's Research & Therapy. 2019 Dec;11:1-0.
125. Nath S, Agholme L, Kurudenkandy FR, Granseth B, Marcusson J, Hallbeck M. Spreading of neurodegenerative pathology via neuron-to-neuron transmission of ?-amyloid. Journal of Neuroscience. 2012 Jun 27;32(26):8767-77.
126. Pereira JB, Janelidze S, Ossenkoppele R, Kvartsberg H, Brinkmalm A, Mattsson-Carlgren N, Stomrud E, Smith R, Zetterberg H, Blennow K, Hansson O. Untangling the association of amyloid-? and tau with synaptic and axonal loss in Alzheimer’s disease. Brain. 2021 Jan 1;144(1):310-24.
127. Lam S, Hérard AS, Boluda S, Petit F, Eddarkaoui S, Cambon K, Picq JL, Buée L, Duyckaerts C, Haïk S. Pathological changes induced by Alzheimer’s brain inoculation in amyloid-beta plaque-bearing mice. Acta Neuropathologica Communications. 2022 Aug 16;10(1):112.
128. Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, Roth K, Aguzzi A, Staufenbiel M, Walker LC, Jucker M. Induction of cerebral ?-amyloidosis: intracerebral versus systemic A? inoculation. Proceedings of the National Academy of Sciences. 2009 Aug 4;106(31):12926-31.
129. Morales R, Duran-Aniotz C, Castilla J, Estrada LD, Soto C. De novo induction of amyloid-? deposition in vivo. Molecular psychiatry. 2012 Dec;17(12):1347-53.
130. Corsi A, Bombieri C, Valenti MT, Romanelli MG. Tau isoforms: gaining insight into MAPT alternative splicing. International Journal of Molecular Sciences. 2022 Dec 6;23(23):15383.
131. Bowles KR, Pugh DA, Oja LM, Jadow BM, Farrell K, Whitney K, Sharma A, Cherry JD, Raj T, Pereira AC, Crary JF. Dysregulated coordination of MAPT exon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD. Acta neuropathologica. 2022 Feb;143:225-43.
132. Rawat P, Sehar U, Bisht J, Selman A, Culberson J, Reddy PH. Phosphorylated tau in Alzheimer’s disease and other tauopathies. International Journal of Molecular Sciences. 2022 Oct 25;23(21):12841.
133. Kelliher MT, Saunders HA, Wildonger J. Microtubule control of functional architecture in neurons. Current opinion in neurobiology. 2019 Aug 1;57:39-45.
134. Soliman A, Bakota L, Brandt R. Microtubule-modulating agents in the fight against neurodegeneration: will it ever work?. Current neuropharmacology. 2022 Mar 3;20(4):782.
135. Tortosa E, Kapitein LC, Hoogenraad CC. Microtubule organization and microtubule-associated proteins (MAPs). Dendrites: Development and Disease. 2016:31-75.
136. Huang HC, Jiang ZF. Accumulated amyloid-? peptide and hyperphosphorylated tau protein: relationship and links in Alzheimer's disease. Journal of Alzheimer's disease. 2009 Jan 1;16(1):15-27.
137. Alonso AD, Cohen LS, Corbo C, Morozova V, ElIdrissi A, Phillips G, Kleiman FE. Hyperphosphorylation of tau associates with changes in its function beyond microtubule stability. Frontiers in cellular neuroscience. 2018 Oct 9;12:338.
138. Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W. Astrocytes are important mediators of A?-induced neurotoxicity and tau phosphorylation in primary culture. Cell death & disease. 2011 Jun;2(6):e167-.
139. Diniz LP, Tortelli V, Matias I, Morgado J, Araujo AP, Melo HM, da Silva GS, Alves-Leon SV, de Souza JM, Ferreira ST, De Felice FG. Astrocyte transforming growth factor beta 1 protects synapses against A? oligomers in Alzheimer's disease model. Journal of Neuroscience. 2017 Jul 12;37(28):6797-809.
140. Zhang H, Wei W, Zhao M, Ma L, Jiang X, Pei H, Cao Y, Li H. Interaction between A? and tau in the pathogenesis of Alzheimer's disease. International journal of biological sciences. 2021;17(9):2181.
141. Kwok JB, Loy CT, Hamilton G, Lau E, Hallupp M, Williams J, Owen MJ, Broe GA, Tang N, Lam L, Powell JF. Glycogen synthase kinase?3? and tau genes interact in Alzheimer's disease. Annals of neurology. 2008 Oct;64(4):446-54.
142. Gerrish A, Russo G, Richards A, Moskvina V, Ivanov D, Harold D, Sims R, Abraham R, Hollingworth P, Chapman J, Hamshere M. The role of variation at A?PP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease. Journal of Alzheimer's Disease. 2012 Jan 1;28(2):377-87.
143. Colom-Cadena M, Gelpi E, Martí MJ, Charif S, Dols-Icardo O, Blesa R, Clarimón J, Lleó A. MAPT H1 haplotype is associated with enhanced ?-synuclein deposition in dementia with Lewy bodies. Neurobiology of aging. 2013 Mar 1;34(3):936-42.
144. Singh S, Singh TG, Rehni AK. An insight into molecular mechanisms and novel therapeutic approaches in epileptogenesis. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2020 Dec 1;19(10):750-79.
145. Hollenbeck PJ, Saxton WM. The axonal transport of mitochondria. Journal of cell science. 2005 Dec 1;118(23):5411-9.
146. Mandelkow EM, Thies E, Mandelkow E. Tau and axonal transport. InAlzheimer’s Disease: Advances in Genetics, Molecular and Cellular Biology 2007 (pp. 237-256). Boston, MA: Springer US.
147. Rebeck GW, Alonzo NC, Berezovska O, Harr SD, Knowles RB, Growdon JH, Hyman BT, Mendez AJ. Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different APOE genotypes. Experimental neurology. 1998 Jan 1;149(1):175-82.
148. Ladu MJ, Reardon C, Van Eldik L, Fagan AM, Bu G, Holtzman D, Getz GS. Lipoproteins in the central nervous system. Annals of the New York Academy of Sciences. 2000 Apr;903(1):167-75.
149. Nishimura M, Satoh M, Matsushita K, Nomura F. How proteomic ApoE serotyping could impact Alzheimer’s disease risk assessment: genetic testing by proteomics. Expert Review of Proteomics. 2014 Aug 1;11(4):405-7.
150. Kraft L, Serpell LC, Atack JR. A biophysical approach to the identification of novel ApoE chemical probes. Biomolecules. 2019 Jan 29;9(2):48.
151. Benitez BA, Karch CM, Cai Y, Jin SC, Cooper B, Carrell D, Bertelsen S, Chibnik L, Schneider JA, Bennett DA, Alzheimer's Disease Neuroimaging Initiative (ADNI). The PSEN1, p. E318G variant increases the risk of Alzheimer's disease in APOE-?4 carriers. PLoS genetics. 2013 Aug 22;9(8):e1003685.
152. Liu CC, Zhao N, Fu Y, Wang N, Linares C, Tsai CW, Bu G. ApoE4 accelerates early seeding of amyloid pathology. Neuron. 2017 Dec 6;96(5):1024-32.
153. Leoni V. The effect of apolipoprotein E (ApoE) genotype on biomarkers of amyloidogenesis, tau pathology and neurodegeneration in Alzheimer's disease. Clinical chemistry and laboratory medicine. 2011 Mar 1;49(3):375-83.
154. Yao ZX, Papadopoulos V. Function of ??amyloid in cholesterol transport: a lead to neurotoxicity. The FASEB Journal. 2002 Oct;16(12):1677-9.
155. Vincent B. Regulation of the ?-secretase ADAM10 at transcriptional, translational and post-translational levels. Brain research bulletin. 2016 Sep 1;126:154-69.
156. Vincent B. Regulation of the ?-secretase ADAM10 at transcriptional, translational and post-translational levels. Brain research bulletin. 2016 Sep 1;126:154-69.
157. Orsucci D, Mancuso M, Caldarazzo Ienco E, Simoncini C, Siciliano G, Bonuccelli U. Vascular factors and mitochondrial dysfunction: a central role in the pathogenesis of Alzheimer's disease. Current neurovascular research. 2013 Feb 1;10(1):76-80.
158. Matsuda M, Shimomura I. Increased oxidative stress in obesity: implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Obesity research & clinical practice. 2013 Sep 1;7(5):e330-41.
159. Grundy SM. Obesity, metabolic syndrome, and cardiovascular disease. The Journal of Clinical Endocrinology & Metabolism. 2004 Jun 1;89(6):2595-600.
160. Husain MA, Laurent B, Plourde M. APOE and Alzheimer’s disease: from lipid transport to physiopathology and therapeutics. Frontiers in neuroscience. 2021 Feb 17;15:630502.
161. Kapasi A, Schneider JA. Vascular contributions to cognitive impairment, clinical Alzheimer's disease, and dementia in older persons. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2016 May 1;1862(5):878-86.
162. Kalaria RN. Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease. Acta neuropathologica. 2016 May;131(5):659-85.
163. Liu X, Chen Z. The pathophysiological role of mitochondrial oxidative stress in lung diseases. Journal of Translational Medicine. 2017 Dec;15:1-3.
164. Bhatia V, Sharma S. Role of mitochondrial dysfunction, oxidative stress and autophagy in progression of Alzheimer's disease. Journal of the neurological sciences. 2021 Feb 15;421:117253.
165. Guedes-Dias P, Holzbaur EL. Axonal transport: Driving synaptic function. Science. 2019 Oct 11;366(6462):eaaw9997.
166. Amadoro G, Corsetti V, Atlante A, Florenzano F, Capsoni S, Bussani R, Mercanti D, Calissano P. Interaction between NH2-tau fragment and A? in Alzheimer's disease mitochondria contributes to the synaptic deterioration. Neurobiology of aging. 2012 Apr 1;33(4):833-e1.
167. Torres AK, Jara C, Park-Kang HS, Polanco CM, Tapia D, Alarcón F, de la Peña A, Llanquinao J, Vargas-Mardones G, Indo JA, Inestrosa NC. Synaptic mitochondria: an early target of amyloid-? and tau in Alzheimer’s disease. Journal of Alzheimer's Disease. 2021 Jan 1;84(4):1391-414