Progression Of Alzheimer's Disease Pathology Research Articles

Plasma Leptin and Alzheimer Protein Pathologies Among Older Adults

Many epidemiologic studies have suggested that low levels of plasma leptin, a major adipokine, are associated with increased risk of Alzheimer disease (AD) dementia and cognitive decline. Nevertheless, the mechanistic pathway linking plasma leptin and AD-related cognitive decline is not yet fully understood. To examine the association of plasma leptin levels with in vivo AD pathologies, including amyloid-beta (Aβ) and tau deposition, through both cross-sectional and longitudinal approaches among cognitively unimpaired older adults. This was a longitudinal cohort study from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease. Data were collected from January 1, 2014, to December 31, 2020, and data were analyzed from July 11 to September 6, 2022. The study included a total of 208 cognitively unimpaired participants who underwent baseline positron emission tomography (PET) scans for brain Aβ deposition. For longitudinal analyses, 192 participants who completed both baseline and 2-year follow-up PET scans for brain Aβ deposition were included. Plasma leptin levels as assessed by enzyme-linked immunosorbent assay. Baseline levels and longitudinal changes of global Aβ and AD-signature region tau deposition measured by PET scans. Among the 208 participants, the mean (SD) age was 66.0 (11.3) years, 114 were women (54.8%), and 37 were apolipoprotein E ε4 carriers (17.8%). Lower plasma leptin levels had a significant cross-sectional association with greater brain Aβ deposition (β = -0.04; 95% CI, -0.09 to 0.00; P = .046), while there was no significant association between plasma leptin levels and tau deposition (β = -0.02; 95% CI, -0.05 to 0.02; P = .41). In contrast, longitudinal analyses revealed that there was a significant association between lower baseline leptin levels and greater increase of tau deposition over 2 years (β = -0.06; 95% CI, -0.11 to -0.01; P = .03), whereas plasma leptin levels did not have a significant association with longitudinal change of Aβ deposition (β = 0.006; 95% CI, 0.00-0.02; P = .27). The present findings suggest that plasma leptin may be protective for the development or progression of AD pathology, including both Aβ and tau deposition.

Osteoclasts Link Dysregulated Peripheral Degradation Processes and Accelerated Progression in Alzheimer's Disease.

The amyloid-β (Aβ) enhances the number and activity of blood monocyte-derived osteoclasts (OCs). Individuals with osteoporosis (OP) face an increased risk of developing dementia or Alzheimer's disease (AD). Despite this association, the contribution of bone-resorbing OCs to the progression of AD pathology remains unclear. Our objective was to investigate the potential impacts of OCs on the development of AD pathology. We conducted targeted analysis of publicly available whole blood transcriptomes from patients with AD to characterize the blood molecular signatures and pathways associated with hyperactive OCs. In addition, we used APP23 transgenic (APP23 TG) AD mouse model to assess the effects of OCs pharmacological blockade on AD pathology and behavior. Patients with AD exhibited increased osteoclastogenesis signature in their blood cells, which appears to be positively correlated with dysfunction of peripheral clearance of Aβ mediated by immune cells. Long-term anti-resorptive intervention with Alendronate inhibited OC activity in APP23 mice, leading to improvements in peripheral monocyte Aβ-degrading enzyme expression, Aβ-deposition, and memory decline. Our findings suggest that OCs have a disease-promoting role in the development and progression of AD, possibly linked to their modulation of peripheral immunity. These findings guide future research to further elucidate the connection between OP and AD pathogenesis, highlighting the potential benefits of preventing OP in alleviating cognitive burden.

C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment. Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD. A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded. Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO). The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS). The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.

The Role of Reactive Oxygen Species in Alzheimer's Disease:from Mechanism to Biomaterials Therapy.

Alzheimer's disease (AD) is a chronic, insidious, and progressive neuro-degenerative disease that remains a clinical challenge for society. The fully approved drug lecanemab exhibits the prospect of therapy against the pathological processes, while debatable adverse events conflict with the drug concentration required for the anticipated therapeutic effects. Reactive oxygen species (ROS) are involved in the pathological progression of AD, as has been demonstrated in much research regarding oxidative stress (OS). The contradiction between anticipated dosage and adverse event may be resolved through targeted transport by biomaterials and get therapeutic effects through pathological progression via regulation of ROS. Besides, biomaterials fix delivery issues by promoting the penetration of drugs across the blood-brain barrier (BBB), protecting the drug from peripheral degradation, and elevating bioavailability. Our goal is to comprehensively understand the mechanisms of ROS in the progression of AD disease and the potential of ROS-related biomaterials in the treatment of AD. This review focuses on OS and its connection with AD and novel biomaterials in recent years against AD via OS to inspire novel biomaterial development. Revisiting these biomaterials and mechanisms associated with OS in AD via thorough investigations presents a considerable potential and bright future for improving effective interventions for AD. This article is protected by copyright. All rights reserved.

The HOPE4MCI study: A randomized double-blind assessment of AGB101 for the treatment of MCI due to AD.

In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD. One hundred and sixty-four participants were randomized to placebo (n = 83) or AGB101 (n = 81), an extended-release formulation of low dose (220mg) levetiracetam. The primary endpoint was the change in Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB) comparing follow up at 18 months to baseline. The goal of the primary efficacy analysis was to estimate the difference between the AGB101 and placebo arms in the mean change of the primary endpoint. The mean change in CDR-SB was estimated to be 1.12 (95% confidence interval [CI]: 0.66, 1.69) for the AGB101 arm and 1.22 (95% CI: 0.75, 1.78) for the placebo arm. The estimated difference between arms is -0.10 (95% CI: -0.85, 0.58), which was not statistically significant. In a prespecified analysis, the difference was -0.45 (95% CI: -1.43, 0.53) for ApoE-4 noncarriers and -0.10 (95% CI: -0.92, 0.72) for apolipoprotein E (ApoE)-4 carriers. The possibility that ApoE-4 carriers and noncarriers will respond differently to therapeutic intervention is consistent with recently reported findings from biologics and the present results show further testing of AGB101 in patients with MCI due to AD who are noncarriers of the ApoeE-4 allele is warranted. Conclusions from the HOPE4MCI study are limited primarily due to the small sample size and results can only be regarded as a guide to future research.

Systematic identification of key basement membrane related genes as potential new biomarkers in Alzheimer's disease

ObjectiveThe study aimed to identify biomarkers associated with basement membranes (BMs)-related genes (BMGs) in Alzheimer's disease (AD) and investigate their potential role in the progression of AD pathology. MethodsGene expression profiles were retrieved from Gene Expression Omnibus database. 222 human BMGs were collected from the relevant literature. Subsequently, the differentially expressed BMGs (DE-BMGs) were filtered, and the key DE-BMGs were identified using weighted gene correlation network analysis (WGCNA) and two machine learning algorithms. The expression levels, diagnostic values, clinical significances, enrichment analyses and regulatory networks of these candidate biomarkers were further examined. ResultsA total of 44 DE-BMGs were acquired by comparing AD temporal cortex with nondemented controls. Using WGCNA and machine learning, versiscan (VCAN), tissue inhibitor of metalloproteinase 1 (TIMP1), structural maintenance of chromosome 3 (SMC3), and laminin β2 (LAMB2) were ultimately identified as candidate biomarkers, and they were verified in a murine model. These biomarkers had high diagnostic value (area under the curve (AUC)＞0.8). The diagnostic value of the four gene combination was then evaluated in multiple databases, yielding AUCs ranging from 0.688 to 1. Furthermore, a meaningful correlation between these biomarkers and AD pathology progression was observed. Finally, comprehensive analyses involving Hallmark pathway enrichment, immune cell infiltration analysis, transcriptional regulatory, and competitive endogenous RNA networks indicated that key DE-BMGs closely correlated with oxidative stress and immune dysfunction. ConclusionOur study comprehensively identified four candidate BMGs and their combination model that play a crucial part in the diagnosis and pathogenesis of AD.

Associations between liver function and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in non-demented adults: The CABLE study.

Liver function has been suggested as a possible factor in the progression of Alzheimer's disease (AD) development. However, the association between liver function and cerebrospinal fluid (CSF) levels of AD biomarkers remains unclear. In this study, we analyzed the data from 1687 adults without dementia from the Chinese Alzheimer's Biomarker and LifestylE study to investigate differences in liver function between pathological and clinical AD groups, as defined by the 2018 National Institute on Aging-Alzheimer's Association Research Framework. We also examined the linear relationship between liver function, CSF AD biomarkers, and cognition using linear regression models. Furthermore, mediation analyses were applied to explore the potential mediation effects of AD pathological biomarkers on cognition. Our findings indicated that, with AD pathological and clinical progression, the concentrations of total protein (TP), globulin (GLO), and aspartate aminotransferase/alanine transaminase (ALT) increased, while albumin/globulin (A/G), adenosine deaminase, alpha-L-fucosidase, albumin, prealbumin, ALT, and glutamate dehydrogenase (GLDH) concentrations decreased. Furthermore, we also identified significant relationships between TP (β = -0.115, pFDR < 0.001), GLO (β = -0.184, pFDR < 0.001), and A/G (β = 0.182, pFDR < 0.001) and CSF β-amyloid1-42 (Aβ1-42 ) (and its related CSF AD biomarkers). Moreover, after 10 000 bootstrapped iterations, we identified a potential mechanism by which TP and GLDH may affect cognition by mediating CSF AD biomarkers, with mediation effect sizes ranging from 3.91% to 16.44%. Overall, our results suggested that abnormal liver function might be involved in the clinical and pathological progression of AD. Amyloid and tau pathologies also might partially mediate the relationship between liver function and cognition. Future research is needed to fully understand the underlying mechanisms and causality to develop an approach to AD prevention and treatment approach.

Intermittent fasting and Alzheimer's disease-Targeting ketone bodies as a potential strategy for brain energy rescue.

Alzheimer's disease (AD) lacks effective clinical treatments. As the disease progresses, the cerebral glucose hypometabolism that appears in the preclinical phase of AD gradually worsens, leading to increasingly severe brain energy disorders. This review analyzes the brain energy deficit in AD and its etiology, brain energy rescue strategies based on ketone intervention, the effects and mechanisms of IF, the differences in efficacy between IF and ketogenic diet and the duality of IF. The evidence suggests that brain energy deficits lead to the development and progression of AD pathology. IF, which improves brain energy impairments by promoting ketone metabolism, thus has good therapeutic potential for AD.

Visualization of the elevated levels of hypochlorous acid in Alzheimer's disease with a ruthenium(II) complex-based luminescence probe

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that devastatingly affects people's lives. Accumulating evidence indicates that the pathological progression of AD is inseparably connected with hypochlorous acid (HClO). However, further exploring the biological function remains an open challenging due to a lack of effective tools to image HClO in AD brains. To this end, a ruthenium(II) luminescence probe, Ru–HClO, is developed for quantitative detection and visualization of HClO in nerve cells and AD brains. Ru–HClO shows quenched luminescence due to the PET process (excited electron transfer from Ru(II) center to diaminomaleonitrile) and the CN bond isomerization in the excited state. The HClO-triggered specific cleavage reaction with Ru–HClO cleaves the CN bond to form highly luminescent Ru–COOH. Ru–HClO shows rapid response speed, high sensitivity and selectivity, excellent biocompatibility, which makes the probe to be applied to semi-quantitative analysis of HClO in nerve cells and high-throughput screening of anti-AD drugs in the AD cell model. Moreover, using Ru–HClO as a probe, present work further validated that the elevated levels of HClO secretion were accompanied by the AD progressed. These findings may provide valuable results for figuring out the biological roles that HClO played in AD but also for accelerating anti-AD therapeutic discovery.

A Study on Autophagy Related Biomarkers in Alzheimer's Disease Based on Bioinformatics.

Alzheimer's disease (AD) is a neurodegenerative disease with an annual incidence increase that poses significant health risks to people. However, the pathogenesis of AD is still unclear. Autophagy, as an intracellular mechanism can degrade damaged cellular components and abnormal proteins, which is closely related to AD pathology. The goal of this work is to uncover the intimate association between autophagy and AD, and to mine potential autophagy-related AD biomarkers by identifying key differentially expressed autophagy genes (DEAGs) and exploring the potential functions of these genes. GSE63061 and GSE140831 gene expression profiles of AD were downloaded from the Gene Expression Omnibus (GEO) database. R language was used to standardize and differentially expressed genes (DEGs) of AD expression profiles. A total of 259 autophagy-related genes were discovered through the autophagy gene databases ATD and HADb. The differential genes of AD and autophagy genes were integrated and analyzed to screen out DEAGs. Then the potential biological functions of DEAGs were predicted, and Cytoscape software was used to detect the key DEAGs. There were ten DEAGs associated with the AD development, including nine up-regulated genes (CAPNS1, GAPDH, IKBKB, LAMP1, LAMP2, MAPK1, PRKCD, RAB24, RAF1) and one down-regulated gene (CASP1). The correlation analysis reveals the potential correlation among 10 core DEAGs. Finally, the significance of the detected DEAGs expression was verified, and the value of DEAGs in AD pathology was detected by the receiver operating characteristic curve. The area under the curve values indicated that ten DEAGs are potentially valuable for the study of the pathological mechanism and may become biomarkers of AD. This pathway analysis and DEAG screening in this study found a strong association between autophagy-related genes and AD, providing new insights into the pathological progression of AD. Exploring the relationship between autophagy and AD: analysis of genes associated with autophagy in pathological mechanisms of AD using bioinformatics. 10 autophagy-related genes play an important role in the pathological mechanisms of AD.

BACE1 SUMOylation deregulates phosphorylation and ubiquitination in Alzheimer's disease pathology.

BACE1 is essential for the generation of amyloid-β (Aβ) that likely initiates the toxicity in Alzheimer's disease (AD). BACE1 activity is mainly regulated by post-translational modifications, but the relationship between these modifications is not fully characterized. Here, we studied the effects of BACE1 SUMOylation on its phosphorylation and ubiquitination. We demonstrate that SUMOylation of BACE1 inhibits its phosphorylation at S498 and its ubiquitination in vitro. Conversely, BACE1 phosphorylation at S498 suppresses its SUMOylation, which results in promoting BACE1 degradation in vitro. Furthermore, an increase in BACE1 SUMOylation is associated with the progression of AD pathology, while its phosphorylation and ubiquitination are decreased in an AD mouse model. Our findings suggest that BACE1 SUMOylation reciprocally influences its phosphorylation and competes against its ubiquitination, which might provide a new insight into the regulations of BACE1 activity and Aβ accumulation.

Development of a novel PET ligand, [11C]GO289 targeting CK2 expressed in the brain

Positron emission tomography (PET) is a powerful imaging tool that enables early in vivo detection of Alzheimer's disease (AD). For this purpose, various PET ligands have been developed to image β-amyloid and tau protein aggregates characteristically found in the brain of AD patients. In this study, we initiated to develop another type of PET ligand that targets protein kinase CK2 (formerly termed as casein kinase II), because its expression level is known to be altered in postmortem AD brains. CK2 is a serine/threonine protein kinase, an important component of cellular signaling pathways that control cellular degeneration. In AD, the CK2 level in the brain is thought to be elevated by its involvement in both phosphorylation of proteins such as tau and neuroinflammation. Decreased CK2 activity and expression levels lead to β-amyloid accumulation. In addition, since CK2 also contributes to the phosphorylation of tau protein, the expression level and activity of CK2 is expected to undergo significant changes during the progression of AD pathology. Furthermore, CK2 could act as a potential target for modulating the inflammatory response in AD. Therefore, PET imaging targeting CK2 expressed in the brain could be a useful another imaging biomarker for AD. We synthesized and radiolabeled a CK2 inhibitor, [11C]GO289, in high yields from its precursor and [11C]methyl iodide under basic conditions. On autoradiography, [11C]GO289 specifically bound to CK2 in both rat and human brain sections. On baseline PET imaging, this ligand entered and rapidly washed out of the rat brain with its peak activity rather being small (SUV < 1.0). However, on blocking, there was no detectable CK2 specific binding signal. Thus, [11C]GO289 may be useful in vitro but not so in vivo in its current formulation. The lack of detectable specific binding signal in the latter may be due to a relatively high component of nonspecific binding signal in the overall rather weak PET signal, or it may also be related to the known fact that ATP can competitively binds to subunits of CK2, reducing its availability for this ligand. In the future, it will be necessary for PET imaging of CK2 to try out different non-ATP competitive formulations of CK2 inhibitor that can also provide significantly higher in vivo brain penetration.

The Role of Iron Metabolism, Lipid Metabolism, and Redox Homeostasis in Alzheimer's Disease: from the Perspective of Ferroptosis.

In the development of Alzheimer's disease (AD), cell death is common. Novel cell death form-ferroptosis is discovered in recent years. Ferroptosis is an iron-regulated programmed cell death mechanism and has been identified in AD clinical samples. Typical characteristics of ferroptosis involve the specific changes in cell morphology, iron-dependent aggregation of reactive oxygen species (ROS) and lipid peroxides, loss of glutathione (GSH), inactivation of glutathione peroxidase 4 (GPX4), and a unique group of regulatory genes. Increasing evidence demonstrates that ferroptosis may be associated with neurological dysfunction in AD. However, the underlying mechanisms have not been fully elucidated. This article reviews the potential role of ferroptosis in AD, the involvement of ferroptosis in the pathological progression of AD through the mechanisms of iron metabolism, lipid metabolism, and redox homeostasis, as well as a range of potential therapies targeting ferroptosis for AD. Intervention strategies based on ferroptosis are promising for Alzheimer's disease treatment at present, but further researches are still needed.

Chronic Treatment with Aβ42 with a Toxic Conformer and LPS Induces Inflammatory Responses in BV-2 Microglia with Dysregulation of Hypoxia-Inducible Factor Expression.

Amyloid β (Aβ) plays a key role in the pathology of Alzheimer's disease (AD) and is toxic owing to its ability to aggregate into oligomers and fibrils. Aβ has high aggregative ability and potent toxicity due to the "toxic turn" at positions 22 and 23. Furthermore, APP knock-in mice producing E22P-Aβ with the toxic turn exhibited AD-related phenotypes such as cognitive impairment, Aβ plaque accumulation, and tau hyperphosphorylation. In these mice, it is suggested that the activation of neuroinflammation and dysregulation of hypoxia-inducible factor (HIF) expression in the hippocampus contribute to the pathogenesis of AD-related phenotype. However, it remains unclear which cells are responsible for the dysregulation of HIF expression and the neuroinflammation which was induced by E22P-Aβ with the toxic turn. Here, we investigated the effects of chronic treatment with E22P-Aβ42 and lipopolysaccharides (LPS) on the inflammatory response in BV-2 microglia. Chronic treatment with E22P-Aβ42 and LPS increased nitric oxide production and the expression of interleukin-6 (IL-6), whereas it reduced the expression of HIF-1α and HIF-3α in BV-2 microglia. The reduction of HIF-1α caused by E22P-Aβ42 and LPS was milder than that caused by LPS. Furthermore, chronic treatment with E22P-Aβ42 and LPS increased the nuclear translocation of nuclear factor-kappaB (NF-κB). E22P-Aβ42 could enhance the inflammatory response of microglia with abnormal HIF signaling and contribute to the progression of AD pathology.

PARP16-Mediated Stabilization of Amyloid Precursor Protein mRNA Exacerbates Alzheimer's Disease Pathogenesis.

The accumulation and deposition of beta-amyloid (Aβ) are key neuropathological hallmarks of Alzheimer's disease (AD). PARP16, a Poly(ADP-ribose) polymerase, is a known tail-anchored endoplasmic reticulum (ER) transmembrane protein that transduces ER stress during pathological processes. Here, we found that PARP16 was significantly increased in the hippocampi and cortices of APPswe/PS1dE9 (APP/PS1) mice and hippocampal neuronal HT22 cells exposed to Aβ, suggesting a positive correlation between the progression of AD pathology and the overexpression of PARP16. To define the effect of PARP16 on AD progression, adeno-associated virus mediated-PARP16 knockdown was used in APP/PS1 mice to investigate the role of PARP16 in spatial memory, amyloid burden, and neuroinflammation. Knockdown of PARP16 partly attenuated impaired spatial memory, as indicated by the Morris water maze test, and decreased amyloid deposition, neuronal apoptosis, and the production of inflammatory cytokines in the brains of APP/PS1 mice. In vitro experiments demonstrated that the knockdown of PARP16 expression rescued neuronal damage and ER stress triggered by Aβ. Furthermore, we discovered that intracellular PARP16 acts as an RNA-binding protein that regulates the mRNA stability of amyloid precursor protein (APP) and protects targeted APP from degradation, thereby increasing APP levels and AD pathology. Our findings revealed an unanticipated role of PARP16 in the pathogenesis of AD, and at least in part, its association with increased APP mRNA stability.

QTC-4-MeOBnE Ameliorated Depressive-Like Behavior and Memory Impairment in 3xTg Mice.

Growing evidence has associated major depressive disorder (MDD) as a risk factor or prodromal syndrome for the occurrence of Alzheimer's disease (AD). Although this dilemma remains open, it is widely shown that a lifetime history of MDD is correlated with faster progression of AD pathology. Therefore, antidepressant drugs with neuroprotective effects could be an interesting therapeutic conception to target this issue simultaneously. In this sense, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) was initially conceived as a multi-target ligand with affinity to β-secretase (BACE), glycogen synthase kinase 3β (GSK3β), and acetylcholinesterase but has also shown secondary effects on pathways involved in neuroinflammation and neurogenesis in preclinical models of AD. Herein, we investigated the effect of QTC-4-MeOBnE (1mg/kg) administration for 45days on depressive-like behavior and memory impairment in 3xTg mice, before the pathology is completely established. The treatment with QTC-4-MeOBnE prevented memory impairment and depressive-like behavior assessed by the Y-Maze task and forced swimming test. This effect was associated with the modulation of plural pathways involved in the onset and progression of AD, in cerebral structures of the cortex and hippocampus. Among them, the reduction of amyloid beta (Aβ) production mediated by changes in amyloid precursor protein metabolism and hippocampal tau phosphorylation through the inhibition of kinases. Additionally, QTC-4-MeOBnE also exerted beneficial effects on neuroinflammation and synaptic integrity. Overall, our studies suggest that QTC-4-MeOBnE has a moderate effect in a transgenic model of AD, indicating that perhaps studies regarding the neuropsychiatric effects as a neuroprotective molecule are more prone to be feasible.

Early alterations in brain glucose metabolism and vascular function in a transgenic rat model of Alzheimer's disease.

Alteration in brain metabolism predates clinical onset of Alzheimer's Disease (AD). Realizing its potential as an early diagnostic marker, however, requires understanding how early AD metabolic dysregulation manifests on non-invasive brain imaging. We presently utilized magnetic resonance imaging and spectroscopy to map glucose and ketone metabolic profiles and image cerebrovascular function in a rat model of early stage AD - 9-month-old TgF344-AD (TgAD) rats - and their age-matched non-transgenic (nTg) littermates. Compared to the nTg rats, TgAD rats displayed attenuation in global cerebral and hippocampal vasoreactivity to hypercapnia, by 49±17% and 58±19%, respectively, while their functional hyperemia to somatosensory stimulation diminished by 69±5%. To assess brain glucose uptake, rats were fasted overnight and then challenged with an intravenous infusion of 2-deoxy-D-glucose (2DG). Compared to their non-transgenic littermates, TgAD rats exhibited 99±10% and 52±5% smaller glucose uptake in the entorhinal cortex and the hippocampus, respectively. Moreover, hippocampal glucose uptake reduction in male TgAD rats compared to the nTg was 54±36% greater than the reduction seen in female TgAD rats. TgAD rats also showed a 59±42% increase in total choline level in the hippocampus, suggesting increased membrane turnover. In combination with our earlier findings of impaired electrophysiological metrics at this early stage of AD pathology progression, our findings suggest that subtle neuronal function alterations that would be difficult to assess in a clinical population may be accompanied by MRI-detectable changes in brain glucose metabolism and cerebrovascular function.

Activation of the TREK-1 Potassium Channel Improved Cognitive Deficits in a Mouse Model of Alzheimer's Disease by Modulating Glutamate Metabolism.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive dysfunction. The glutamate (Glu) metabolic pathway may be a major contributor to the memory dysfunction associated with AD. The TWIK-related potassium channel-1 (TREK-1) protects against brain ischemia, but any specific role for the channel in AD remains unknown. In this study, we used SAMP8 mice as an AD model and age-matched SAMR1 mice as controls. We explored the trends of changes in TREK-1 channel activity and the levels of AD-related molecules in the brains of SAMP8 mice. We found that the expression level of TREK-1 increased before 3months of age and then began to decline. The levels of Tau and Glu increased with age whereas the acetylcholine level decreased with age. α-Linolenic acid (ALA), an activator of the TREK-1 channel, significantly increased the TREK-1 level, and improved the learning and memory deficits of SAMP8 mice aged 6months. The mechanism in play may involve the Glu metabolic pathway. After activation of the TREK-1 channel, damaged neurons and astrocytes were rescued, the levels of Glu and the N-methyl-D-aspartate receptor were downregulated, and the level of glutamate transporter-1 was upregulated. These findings suggest that TREK-1 plays a crucial role in the pathological progression of AD; activation of the TREK-1 channel improved cognitive deficits in SAMP8 mice via a mechanism that involved Glu metabolism. The TREK-1 potassium channel may thus be a valuable therapeutic target in AD patients.

MiR-30a-5p induces Aβ production via inhibiting the nonamyloidogenic pathway in Alzheimer’s disease

Alzheimer's disease (AD) pathogenesis is known to involve a dysregulation of microRNA expression, and these intricate transcriptional cascades between multiple pathological manifestations affect brain homeostasis. Previous studies have revealed that miR-30a-5p participates in neuronal damage and is upregulated in amyloid beta-peptide (Aβ)-induced models. However, its involvement in cognition dysfunction and the AD pathogenic process remains unclear. In the present study, we investigated the mechanisms underlying miR-30a-5p involvement in AD, and its potential as a therapeutic target. Our results reveal that miR-30a-5p was substantially upregulated during the pathological progression of AD, presenting as an increased level in the cortex and hippocampus of APP/PS1 and five familial AD mice, AD cells, and the plasma of AD patients. miR-30a-5p overexpression also induced neuronal injury and apoptosis in AD cells. Mechanistically, miR-30a-5p negatively regulated ADAM10 and SIRT1 by directly binding to their 3′-untranslated regions. A possible association between SIRT1 and ADAM10 was observed via their rescue of miR-30a-5p-induced RARβ downregulation. Interestingly, miR-30a-5p was observed to inhibit the nonamyloidogenic pathway by down regulating ADAM10 and SIRT1, thus promoting Aβ1–42 overproduction. In APP/PS1 mice, knockdown of miR-30a-5p ameliorated cognitive dysfunctions and neurodegenerative changes, suppressed Aβ accumulation, and inhibited Aβ1–42 generation by enhancing the nonamyloidogenic pathway via upregulation of ADAM10 and SIRT1. However, these improvements were blocked by ADAM10 and SIRT1 silencing. In conclusion, the present study implicates dysregulation of the miR-30a-5p/ ADAM10/ SIRT1 pathway as a critical mediator of AD pathogenesis, highlighting the importance of epigenetics and identifying novel therapeutic targets in the nonamyloidogenic pathway.

Microglia and CD206+ border-associated mouse macrophages maintain their embryonic origin during Alzheimer's disease.

Brain microglia and border-associated macrophages (BAMs) display distinct spatial, developmental, and phenotypic features. Although at steady state, the origins of distinct brain macrophages are well-documented, the dynamics of their replenishment in neurodegenerative disorders remain elusive, particularly for activated CD11c+ microglia and BAMs. In this study, we conducted a comprehensive fate-mapping analysis of murine microglia and BAMs and their turnover kinetics during Alzheimer's disease (AD) progression. We used a novel inducible AD mouse model to investigate the contribution of bone marrow (BM) cells to the pool of fetal-derived brain macrophages during the development of AD. We demonstrated that microglia remain a remarkably stable embryonic-derived population even during the progression of AD pathology, indicating that neither parenchymal macrophage subpopulation originates from, nor is replenished by, BM-derived cells. At the border-associated brain regions, bona fide CD206+ BAMs are minimally replaced by BM-derived cells, and their turnover rates are not accelerated by AD. In contrast, all other myeloid cells are swiftly replenished by BM progenitors. This information further elucidates the turnover kinetics of these cells not only at steady state, but also in neurodegenerative diseases, which is crucial for identifying potential novel therapeutic targets.