ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aß Secretion.

Human apolipoprotein E (ApoE) apolipoprotein is primarily expressed in three isoforms (ApoE2, ApoE3, and ApoE4) that differ only by two residues. ApoE4 constitutes the most important genetic risk factor for Alzheimer's disease (AD), ApoE3 is neutral, and ApoE2 is protective. How ApoE isoforms influence AD pathogenesis, however, remains unclear. Using ES-cell-derived human neurons, we show that ApoE secreted by glia stimulates neuronal Aß production with an ApoE4 > ApoE3 > ApoE2 potency rank order. We demonstrate that ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases. Activated ERK1/2 induces cFos phosphorylation, stimulating the transcription factor AP-1, which in turn enhances transcription of amyloid-ß precursor protein (APP) and thereby increases amyloid-ß levels. This molecular mechanism also regulates APP transcription in mice in vivo. Our data describe a novel signal transduction pathway in neurons whereby ApoE activates a non-canonical MAP kinase cascade that enhances APP transcription and amyloid-ß synthesis.

Lung endothelium, tau, and amyloids in health and disease.

Lung endothelia in the arteries, capillaries, and veins are heterogeneous in structure and function. Lung capillaries in particular represent a unique vascular niche, with a thin yet highly restrictive alveolar-capillary barrier that optimizes gas exchange. Capillary endothelium surveys the blood while simultaneously interpreting cues initiated within the alveolus and communicated via immediately adjacent type I and type II epithelial cells, fibroblasts, and pericytes. This cell-cell communication is necessary to coordinate the immune response to lower respiratory tract infection. Recent discoveries identify an important role for the microtubule-associated protein tau that is expressed in lung capillary endothelia in the host-pathogen interaction. This endothelial tau stabilizes microtubules necessary for barrier integrity, yet infection drives production of cytotoxic tau variants that are released into the airways and circulation, where they contribute to end-organ dysfunction. Similarly, beta-amyloid is produced during infection. Beta-amyloid has antimicrobial activity, but during infection it can acquire cytotoxic activity that is deleterious to the host. The production and function of these cytotoxic tau and amyloid variants are the subject of this review. Lung-derived cytotoxic tau and amyloid variants are a recently discovered mechanism of end-organ dysfunction, including neurocognitive dysfunction, during and in the aftermath of infection.

A possible mechanism for the enhanced toxicity of beta-amyloid protofibrils in Alzheimer's disease.

The amyloid-beta peptide (Aß) is a driver of Alzheimer's disease (AD). Aß monomers can aggregate and form larger soluble (oligomers/protofibrils) and insoluble (fibrils) forms. There is evidence that Aß protofibrils are the most toxic form, but the reasons are not known. Consistent with a critical role for this form of Aß in AD, a recently FDA-approved therapeutic antibody targeted against protofibrils, lecanemab, slows the progression of AD in patients. The plasma contact system, which can promote coagulation and inflammation, has been implicated in AD pathogenesis. This system is activated by Aß which could lead to vascular and inflammatory pathologies associated with AD. We show here that the contact system is preferentially activated by protofibrils of Aß. Aß protofibrils bind to coagulation factor XII and high molecular weight kininogen and accelerate the activation of the system. Furthermore, lecanemab blocks Aß protofibril activation of the contact system. This work provides a possible mechanism for Aß protofibril toxicity in AD and why lecanemab is therapeutically effective.

Lipid imaging of Alzheimer's disease pathology.

Alzheimer's disease (AD) affects one in eight individuals over 65 and poses an immense societal challenge. AD pathology is characterized by the formation of beta-amyloid plaques and Tau tangles in the brain. While some disease-modifying treatments targeting beta-amyloid are emerging, the exact chain of events underlying the pathogenesis of this disease remains unclear. Brain lipids have long been implicated in AD pathology, though their role in AD pathogenesis remains not fully resolved. Significant advancements in mass spectrometry imaging (MSI) allow to detail spatial lipid regulations in biological tissues at the low um scale. In this issue, Huang et al. resolve spatial lipid patterns in human AD brain and genetic mouse models using desorption electrospray ionization (DESI)-based MSI integrated with other spatial techniques such as imaging mass cytometry of correlative protein signatures. Those spatial multiomics experiments identify plaque-associated lipid regulations that are dependent on progressing plaque pathology in both mouse models and the human brain. Of those lipid species, particularly pro-inflammatory lysophospholipids have been implicated in AD pathology through their interaction with both aggregating Aß and microglial activation through lipid sensing surface receptors. Together, this study provides further insight into how brain lipid homeostasis is linked to progressing AD pathology, and thereby highlights the potential of MSI-based spatial lipidomics as an emerging spatial biology technology for biomedical research.

Midlife insulin resistance, APOE genotype, and change in late-life brain beta-amyloid accumulation - A 5-year follow-up [11C]PIB-PET study.

We studied if midlife insulin resistance (IR) and APOE genotype would predict brain beta-amyloid (Aß) accumulation and Aß change in late-life in 5-year follow-up [11C]PIB-PET study. 43 dementia-free participants were scanned twice with [11C]PIB-PET in their late-life (mean age at follow-up 75.4 years). Participants were recruited from the Finnish Health2000 study according to their HOMA-IR values measured in midlife (mean age at midlife 55.4 years; IR+ group, HOMA-IR > 2.17; IR- group, HOMA-IR <1.25), and their APOEε4 genotype. At late-life follow-up, [11C]PIB-PET composite SUVr was significantly higher in IR+ group than IR- group (median 2.3 (interquartile range 1.7-3.3) vs. 1.7 (1.5-2.4), p = 0.03). There was no difference between IR- and IR+ groups in [11C]PIB-PET SUVr 5-year change, but the change was significantly higher in IR+/APOEε4+ group (median change 0.8 (0.60-1.0)) than in IR-/APOEε4- (0.28 (0.14-0.47), p = 0.02) and in IR+/APOEε4- group (0.24 (0.06-0.40), p = 0.046). These results suggest that APOEε4 carriers with midlife IR are at increased risk for late-life Aß accumulation.

Similar brain proteomic signatures in Alzheimer's disease and epilepsy.

The prevalence of epilepsy is increased among Alzheimer's Disease (AD) patients and cognitive impairment is common among people with epilepsy. Epilepsy and AD are linked but the shared pathophysiological changes remain poorly defined. We aim to identify protein differences associated with epilepsy and AD using published proteomics datasets. We observed a highly significant overlap in protein differences in epilepsy and AD: 89% (689/777) of proteins altered in the hippocampus of epilepsy patients were significantly altered in advanced AD. Of the proteins altered in both epilepsy and AD, 340 were altered in the same direction, while 216 proteins were altered in the opposite direction. Synapse and mitochondrial proteins were markedly decreased in epilepsy and AD, suggesting common disease mechanisms. In contrast, ribosome proteins were increased in epilepsy but decreased in AD. Notably, many of the proteins altered in epilepsy interact with tau or are regulated by tau expression. This suggests that tau likely mediates common protein changes in epilepsy and AD. Immunohistochemistry for Aß and multiple phosphorylated tau species (pTau396/404, pTau217, pTau231) showed a trend for increased intraneuronal pTau217 and pTau231 but no phosphorylated tau aggregates or amyloid plaques in epilepsy hippocampal sections. Our results provide insights into common mechanisms in epilepsy and AD and highlights the potential role of tau in mediating common pathological protein changes in epilepsy and AD.

Pre-clinical evaluation of 99mTc-labeled chalcone derivative for amyloid-ß imaging post-head trauma.

Aß42 plaque formation is one of the preliminary pathologic events that occur post traumatic brain injury (TBI) which is also among the most noteworthy hallmarks of AD. Their pre symptomatic detection is therefore vital for better disease management. Chalcone-picolinic acid chelator derivative, 6-({[(6-carboxypyridin-2-yl)methyl](2-{4-[(2E)-3-[4-(dimethyl amino)phenyl]prop-2-enoyl]phenoxy}ethyl)amino}methyl)pyridine-2-carboxylic acid, Py-chal was synthesized to selectively identify amyloid plaques formed post head trauma using SPECT imaging by stable complexation to 99mTc with > 97% efficiency without compromising amyloid specificity. The binding potential of the Py-chal ligand to amyloid plaques remained high as confirmed by in vitro binding assay and photophysical spectra. Further, the Py-chal complex stained amyloid aggregates in the brain sections of rmTBI mice model. In vivo scintigraphy in TBI mice model displayed high uptake followed by high retention while the healthy rabbits displayed higher brain uptake followed by a rapid washout attributed to absence of amyloid plaques. Higher uptake in brain of TBI model was also confirmed by ex vivo biodistribution analysis wherein brain uptake of 3.38 ± 0.2% ID/g at 2 min p.i. was observed for TBI mice model. This was followed by prolonged retention and more than twofold higher activity as compared to sham mice brain. This preliminary data suggests the specificity of the radiotracer for amyloid detection post head trauma and applicability of 99mTc labeled Py-chal complex for TBI-induced ß-amyloid SPECT imaging.

Exploring Bimetallic Nanoparticles in Alzheimer's Therapy: A Novel Bio-Assisted Synthesis with Multitarget Potential.

Unlocking the potential of metal nanoparticles (NPs) in biomedical applications represents a leading endeavor in contemporary research. Among these, gold NPs (AuNPs) and silver NPs (AgNPs) have shown promising strides in combatting complex neurodegenerative ailments like Alzheimer's disease. Yet, the unexplored realm of bimetallic Au/Ag-NP harbors immense potential, concealing undiscovered opportunities for enhanced therapeutic effectiveness through the synergistic interaction of metal ions. Nonetheless, the limitations of traditional synthesis methods have restricted the preparation, biocompatibility, and versatility of these NPs, prompting an urgent requirement for innovative approaches. Biobased synthetic methodologies have emerged as a noteworthy solution to address these challenges. Our study ventures into uncharted terrain, harnessing collagen-mimicking peptide nanofibers as a bioactive template for the synthesis of bimetallic NPs. These green NPs exhibit remarkable activity in inhibiting amyloid ß (Aß) protein aggregation with almost 74% inhibition, surpassing the individual impacts of Au and Ag NPs, which show inhibition percentages of 66 and 43, respectively. The bimetallic Au/Ag-NPs not only demonstrate powerful inhibition of Aß, but they also demonstrate inhibitory activity against esterase (∼50%) and against reactive oxygen species (ROS) (∼75%), metamorphosing into multifaceted therapeutic agents for Alzheimer's disease. Au/Ag-NPs have proven highly beneficial in surpassing cellular barriers, as evidenced by studies on tissue penetration, 3D uptake, and endosomal escape, and these attributes also hold promise for the future treatment modalities. The findings indicate that the intrinsic traits of Au/Ag-NPs provide numerous mechanistic benefits, such as inhibiting Aß and acetylcholinesterase (AChE), and reducing stress related to ROS, in addition to their advantageous internalization properties. This research represents a notable advancement in the development of multitargeted treatments for neurodegenerative disorders using bimetallic NPs, diverging from the prevalent emphasis on AuNPs in the current literature.

A conformationally-locked p-hydroxybenzylidene imidazolinone derivative for detecting Aß42 aggregation.

Alzheimer's disease (AD) is a common type of neurodegenerative disease, which can only be symptomatically relieved but does not yet have a cure. Among the different Aß species, amyloid-ß 42 (Aß42) aggregates are proposed to be more neurotoxic than that of Aß40, and oligomeric Aß42 is thought to play a harmful role in the pathophysiology of AD. Therefore, the detection of Aß42 aggregation is very meaningful in the AD field. We herein report a conformationally-locked p- hydroxybenzylidene imidazolinone derivative, BDI, which exhibits selectivity and specificity towards Aß42 aggregation and remarkable fluorescent enhancement with a large Stokes shift (more than 100 nm). In the fluorescent co-localization study, BDI can sensitively detect a large population of Aß42 aggregation over that of Aß40 in the brain tissues of AD transgenic mouse models. Therefore, this new probe could provide a useful tool for the rapid detection of important Aß species in AD.

Discovery of cinnamamide/ester triazole hybrids as potential treatment for Alzheimer's disease.

Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aß-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aß toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aß deposition in Aß1-42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.

Midlife cumulative deficit frailty predicts Alzheimer's disease-related plasma biomarkers in older adults.

BACKGROUND: The study explores whether frailty at midlife predicts mortality and levels of biomarkers associated with Alzheimer's disease and related dementias (ADRD) and neurodegeneration by early old age. We also examine the heritability of frailty across this age period. METHODS: Participants were 1,286 community-dwelling men from the Vietnam Era Twin Study of Aging at average ages 56, 62 and 68, all without ADRD at baseline. The cumulative deficit frailty index (FI) comprised 37 items assessing multiple physiological systems. Plasma biomarkers at age 68 included beta-amyloid (Aß40, Aß42), total tau (t-tau) and neurofilament light chain (NfL). RESULTS: Being frail doubled the risk of all-cause mortality by age 68 (OR = 2.44). Age 56 FI significantly predicted age 68 NfL (P = 0.014), Aß40 (P = 0.001) and Aß42 (P = 0.023), but not t-tau. Age 62 FI predicted all biomarkers at age 68: NfL (P = 0.023), Aß40 (P = 0.002), Aß42 (P = 0.001) and t-tau (P = 0.001). Age 68 FI scores were associated with age 68 levels of NfL (P = 0.027), Aß40 (P < 0.001), Aß42 (P = 0.001) and t-tau (P = 0.003). Genetic influences accounted for 45-48% of the variance in frailty and significantly contributed to its stability across 11 years. CONCLUSIONS: Frailty during one's 50s doubled the risk of mortality by age 68. A mechanism linking frailty and ADRD may be through its associations with biomarkers related to neurodegeneration. Cumulative deficit frailty increases with age but remains moderately heritable across the age range studied. With environmental factors accounting for about half of its variance, early interventions aimed at reducing frailty may help to reduce risk for ADRD.

APOE2 protects against Aß pathology by improving neuronal mitochondrial function through ERRα signaling.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear. METHODS: We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively. RESULTS: The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aß). Moreover, APOE2 overexpression alleviates Aß1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aß1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aß injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice. CONCLUSIONS: APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.

Polar lipids modify Alzheimer's Disease pathology by reducing astrocyte pro-inflammatory signaling through platelet-activating factor receptor (PTAFR) modulation.

BACKGROUND: Pro-inflammatory processes triggered by the accumulation of extracellular amyloid beta (Aß) peptides are a well-described pathology in Alzheimer's disease (AD). Activated astrocytes surrounding Aß plaques contribute to inflammation by secreting proinflammatory factors. While astrocytes may phagocytize Aß and contribute to Aß clearance, reactive astrocytes may also increase Aß production. Therefore, identifying factors that can attenuate astrocyte activation and neuroinflammation and how these factors influence pro-inflammatory pathways is important for developing therapeutic and preventive strategies in AD. Here, we identify the platelet-activating factor receptor (PTAFR) pathway as a key mediator of astrocyte activation. Intriguingly, several polar lipids (PLs) have exhibited anti-inflammatory protective properties outside the central nervous system through their inhibitory effect on the PTAFR pathway. Thus, we additionally investigated whether different PLs also exert inhibitory effects on the PAF pathway in astrocytes and whether their presence influences astrocytic pro-inflammatory signaling and known AD pathologies in vitro. METHODS: PLs from salmon and yogurt were extracted using novel food-grade techniques and their fatty acid profile was determined using LC/MS. The effect of PLs on parameters such as astrocyte activation and generation of oxygen species (ROS) was assessed. Additionally, effects of the secretome of astrocytes treated with these polar lipids on aged neurons was measured. RESULTS: We show that PLs obtained from salmon and yogurt lower astrocyte activation, the generation of reactive oxygen species (ROS), and extracellular Aß accumulation. Cell health of neurons exposed to the secretome of astrocytes treated with salmon-derived PLs and Aß was less affected than those treated with astrocytes exposed to Aß only. CONCLUSION: Our results highlight a novel underlying mechanism, why consuming PL-rich foods such as fish and dairy may reduce the risk of developing dementia and associated disorders.

Tau seeds from Alzheimer's disease brains trigger tau spread in macaques while oligomeric-Aß mediates pathology maturation.

INTRODUCTION: The "prion-like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid-ß (Aß) have never been experimentally studied in primates phylogenetically close to humans. METHODS: We injected 17 macaques in the entorhinal cortex with nanograms of seeding-competent tau aggregates purified from AD brains or control extracts from aged-matched healthy brains, with or without intracerebroventricular co-injections of oligomeric-Aß. RESULTS: Pathological tau injection increased cerebrospinal fluid (CSF) p-tau181 concentration after 18 months. Tau pathology spreads from the entorhinal cortex to the hippocampal trisynaptic loop and the cingulate cortex, resuming the experimental progression of Braak stage I to IV. Many AD-related molecular networks were impacted by tau seeds injections regardless of Aß injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total-tau concentration, and pre- and postsynaptic degeneration only in Aß co-injected macaques. DISCUSSION: Oligomeric-Aß mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading. HIGHLIGHTS: This study supports the "prion-like" properties of misfolded tau extracted from AD brains. This study empirically validates the Braak staging in an anthropomorphic brain. This study highlights the role of oligomeric Aß in driving the maturation and toxicity of tau pathology. This work establishes a novel animal model of early sporadic AD that is closer to the human pathology.

Atrophy links lower novelty-related locus coeruleus connectivity to cognitive decline in preclinical AD.

INTRODUCTION: Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated the contribution of LC-MTL functional connectivity (FCLC-MTL) on cortical atrophy across Braak stage regions and its impact on cognition. METHODS: We analyzed functional magnetic resonance imaging and amyloid beta (Aß) positron emission tomography data from 128 cognitively normal participants, associating novelty-related FCLC-MTL with longitudinal atrophy and cognition with and without Aß moderation. RESULTS: Cross-sectionally, lower FCLC-MTL was associated with atrophy in Braak stage II regions. Longitudinally, atrophy in Braak stage 2 to 4 regions related to lower baseline FCLC-MTL at elevated levels of Aß, but not to other regions. Atrophy in Braak stage 2 regions mediated the relation between FCLC-MTL and subsequent cognitive decline. DISCUSSION: FCLC-MTL is implicated in Aß-related cortical atrophy, suggesting that LC-MTL connectivity could confer neuroprotective effects in preclinical AD. HIGHLIGHTS: Novelty-related functional magnetic resonance imaging (fMRI) LC-medial temporal lobe (MTL) connectivity links to longitudinal Aß-dependent atrophy. This relationship extended to higher Braak stage regions with increasing Aß burden. Longitudinal MTL atrophy mediated the LC-MTL connectivity-cognition relationship. Our findings mirror the animal data on MTL atrophy following NE signal dysfunction.

Conformational Changes and Unfolding of ß-Amyloid Substrates in the Active Site of γ-Secretase.

Alzheimer's disease (AD) is the leading cause of dementia and is characterized by a presence of amyloid plaques, composed mostly of the amyloid-ß (Aß) peptides, in the brains of AD patients. The peptides are generated from the amyloid precursor protein (APP), which undergoes a sequence of cleavages, referred as trimming, performed by γ-secretase. Here, we investigated conformational changes in a series of ß-amyloid substrates (from less and more amyloidogenic pathways) in the active site of presenilin-1, the catalytic subunit of γ-secretase. The substrates are trimmed every three residues, finally leading to Aß40 and Aß42, which are the major components of amyloid plaques. To study conformational changes, we employed all-atom molecular dynamics simulations, while for unfolding, we used steered molecular dynamics simulations in an implicit membrane-water environment to accelerate changes. We have found substantial differences in the flexibility of extended C-terminal parts between more and less amyloidogenic pathway substrates. We also propose that the positively charged residues of presenilin-1 may facilitate the stretching and unfolding of substrates. The calculated forces and work/energy of pulling were exceptionally high for Aß40, indicating why trimming of this substrate is so infrequent.

Sphingosine-1-phosphate Decreases Erythrocyte Dysfunction Induced by ß-Amyloid.

Amyloid beta peptides (Aß) have been identified as the main pathogenic agents in Alzheimer's disease (AD). Soluble Aß oligomers, rather than monomer or insoluble amyloid fibrils, show red blood cell (RBC) membrane-binding capacity and trigger several morphological and functional alterations in RBCs that can result in impaired oxygen transport and delivery. Since bioactive lipids have been recently proposed as potent protective agents against Aß toxicity, we investigated the role of sphingosine-1-phosphate (S1P) in signaling pathways involved in the mechanism underlying ATP release in Ab-treated RBCs. In RBCs following different treatments, the ATP, 2,3 DPG and cAMP levels and caspase 3 activity were determined by spectrophotometric and immunoassay. S1P rescued the inhibition of ATP release from RBCs triggered by Ab, through a mechanism involving caspase-3 and restoring 2,3 DPG and cAMP levels within the cell. These findings reveal the molecular basis of S1P protection against Aß in RBCs and suggest new therapeutic avenues in AD.

Salivary Biomarkers for Alzheimer's Disease: A Systematic Review with Meta-Analysis.

Alzheimer's Disease (AD) is the most common neurodegenerative disease which manifests with progressive cognitive impairment, leading to dementia. Considering the noninvasive collection of saliva, we designed the systematic review to answer the question "Are salivary biomarkers reliable for the diagnosis of Alzheimer's Disease?" Following the inclusion and exclusion criteria, 30 studies were included in this systematic review (according to the PRISMA statement guidelines). Potential biomarkers include mainly proteins, metabolites and even miRNAs. Based on meta-analysis, in AD patients, salivary levels of beta-amyloid42 and p-tau levels were significantly increased, and t-tau and lactoferrin were decreased at borderline statistical significance. However, according to pooled AUC, lactoferrin and beta-amyloid42 showed a significant predictive value for salivary-based AD diagnosis. In conclusion, potential markers such as beta-amyloid42, tau and lactoferrin can be detected in the saliva of AD patients, which could reliably support the early diagnosis of this neurodegenerative disease.

The Single Toxin Origin of Alzheimer's Disease and Other Neurodegenerative Disorders Enables Targeted Approach to Treatment and Prevention.

New data suggest that the aggregation of misfolded native proteins initiates and drives the pathogenic cascade that leads to Alzheimer's disease (AD) and other age-related neurodegenerative disorders. We propose a unifying single toxin theory of brain neurodegeneration that identifies new targets and approaches to the development of disease-modifying treatments. An extensive body of genetic evidence suggests soluble aggregates of beta-amyloid (Aß) as the primary neurotoxin in the pathogenesis of AD. New insights from fluid biomarkers, imaging, and clinical studies provide further evidence for the decisive impact of toxic Aß species in the initiation and progression of AD. Understanding the distinct roles of soluble and insoluble amyloid aggregates on AD pathogenesis has been the key missing piece of the Alzheimer's puzzle. Data from clinical trials with anti-amyloid agents and recent advances in the diagnosis of AD demonstrate that the driving insult in biologically defined AD is the neurotoxicity of soluble Aß aggregates, called oligomers and protofibrils, rather than the relatively inert insoluble mature fibrils and amyloid plaques. Amyloid oligomers appear to be the primary factor causing the synaptic impairment, neuronal stress, spreading of tau pathology, and eventual cell death that lead to the clinical syndrome of AD dementia. All other biochemical effects and neurodegenerative changes in the brain that are observed in AD are a response to or a downstream effect of this initial toxic insult by oligomers. Other neurodegenerative disorders follow a similar pattern of pathogenesis, in which normal brain proteins with important biological functions become trapped in the aging brain due to impaired clearance and then misfold and aggregate into neurotoxic species that exhibit prion-like behavior. These aggregates then spread through the brain and cause disease-specific neurodegeneration. Targeting the inhibition of this initial step in neurodegeneration by blocking the misfolding and aggregation of healthy proteins has the potential to slow or arrest disease progression, and if treatment is administered early in the course of AD and other neurodegenerative disorders, it may delay or prevent the onset of clinical symptoms.

Melatonin Inhibits Hypoxia-Induced Alzheimer's Disease Pathogenesis by Regulating the Amyloidogenic Pathway in Human Neuroblastoma Cells.

Stroke and Alzheimer's disease (AD) are prevalent age-related diseases; however, the relationship between these two diseases remains unclear. In this study, we aimed to investigate the ability of melatonin, a hormone produced by the pineal gland, to alleviate the effects of ischemic stroke leading to AD by observing the pathogenesis of AD hallmarks. We utilized SH-SY5Y cells under the conditions of oxygen-glucose deprivation (OGD) and oxygen-glucose deprivation and reoxygenation (OGD/R) to establish ischemic stroke conditions. We detected that hypoxia-inducible factor-1α (HIF-1α), an indicator of ischemic stroke, was highly upregulated at both the protein and mRNA levels under OGD conditions. Melatonin significantly downregulated both HIF-1α mRNA and protein expression under OGD/R conditions. We detected the upregulation of ß-site APP-cleaving enzyme 1 (BACE1) mRNA and protein expression under both OGD and OGD/R conditions, while 10 µM of melatonin attenuated these effects and inhibited beta amyloid (Aß) production. Furthermore, we demonstrated that OGD/R conditions were able to activate the BACE1 promoter, while melatonin inhibited this effect. The present results indicate that melatonin has a significant impact on preventing the aberrant development of ischemic stroke, which can lead to the development of AD, providing new insight into the prevention of AD and potential stroke treatments.