Aβ Metabolism Research Articles

Amyloid-beta metabolism in age-related neurocardiovascular diseases.

Epidemiological evidence suggests the presence of common risk factors for the development and prognosis of both cardio- and cerebrovascular diseases, including stroke, Alzheimer's disease, vascular dementia, heart, and peripheral vascular diseases. Accumulation of harmful blood signals may induce organotypic endothelial dysfunction affecting blood-brain barrier function and vascular health in age-related diseases. Genetic-, age-, lifestyle- or cardiovascular therapy-associated imbalance of amyloid-beta (Aβ) peptide metabolism in the brain and periphery may be the missing link between age-related neurocardiovascular diseases. Genetic polymorphisms of genes related to Aβ metabolism, lifestyle modifications, drugs used in clinical practice, and Aβ-specific treatments may modulate Aβ levels, affecting brain, vascular, and cardiac diseases. This narrative review elaborates on the effects of interventions on Aβ metabolism in the brain, cerebrospinal fluid, blood, and peripheral heart or vascular tissues. Implications for clinical applicability, gaps in knowledge, and future perspectives of Aβ as the link among age-related neurocardiovascular diseases are also discussed.

Therapeutic Challenges Derived from the Interaction Among Apolipoprotein E, Cholesterol, and Amyloid in Alzheimer’s Disease

The isoform E4 of the Apolipoprotein E (ApoE) represents one of the strongest genetic risk factors for late-onset Alzheimer’s disease (AD). ApoE has key roles in cholesterol transport and amyloid-β (Aβ) metabolism, which are both central to AD pathogenesis. The E4 isoform has been implicated in reduced cholesterol homeostasis, increased Aβ aggregation, and heightened tau phosphorylation, contributing to amyloid plaques and neurodegeneration. This manuscript examines the complex interactions among ApoE isoforms, cholesterol metabolism, and amyloid pathology. Moreover, the therapeutic challenges associated with lipid-lowering agents (e.g., statins, PCSK9 inhibitors), anti-amyloid immunotherapies, and anticoagulants are described, focusing on ApoE4 carriers. Decision-making challenges are discussed by analyzing the pros and cons of these therapies.

Exploring the role of HIF-1α on pathogenesis in Alzheimer's disease and potential therapeutic approaches.

Hypoxia-inducible factor 1α (HIF-1α) is a crucial transcription factor that regulates cellular responses to low oxygen levels (hypoxia). In Alzheimer's disease (AD), emerging evidence suggests a significant involvement of HIF-1α in disease pathogenesis. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to neuronal dysfunction and cognitive decline. HIF-1α is implicated in AD through its multifaceted roles in various cellular processes. Firstly, in response to hypoxia, HIF-1α promotes the expression of genes involved in angiogenesis, which is crucial for maintaining cerebral blood flow and oxygen delivery to the brain. However, in the context of AD, dysregulated HIF-1α activation may exacerbate cerebral hypoperfusion, contributing to neuronal damage. Moreover, HIF-1α is implicated in the regulation of Aβ metabolism. It can influence the production and clearance of Aβ peptides, potentially modulating their accumulation and toxicity in the brain. Additionally, HIF-1α activation has been linked to neuroinflammation, a key feature of AD pathology. It can promote the expression of pro-inflammatory cytokines and exacerbate neuronal damage. Furthermore, HIF-1α may play a role in synaptic plasticity and neuronal survival, which are impaired in AD. Dysregulated HIF-1α signaling could disrupt these processes, contributing to cognitive decline and neurodegeneration. Overall, the involvement of HIF-1α in various aspects of AD pathophysiology highlights its potential as a therapeutic target. Modulating HIF-1α activity could offer novel strategies for mitigating neurodegeneration and preserving cognitive function in AD patients. However, further research is needed to elucidate the precise mechanisms underlying HIF-1α dysregulation in AD and to develop targeted interventions.

ZiBu PiYin recipe regulates central and peripheral Aβ metabolism and improves diabetes-associated cognitive decline in ZDF rats

Ethnopharmacological relevanceCognitive impairment caused by central neuropathy in type 2 diabetes mellitus (T2DM), namely diabetes-associated cognitive decline (DACD), is one of the common complications in patients with T2DM. Studies have shown that brain β-amyloid (Aβ) deposition is a typical pathological change in patients with DACD, and that there is a close relationship between intestinal microorganisms and cognitive impairment. However, the specific mechanism(s) of alteration in Aβ metabolism in DACD, and of the correlation between Aβ metabolism and intestinal microorganisms remain unknown. Aim of the studyRevealing the mechanism of ZBPYR regulating Aβ metabolism and providing theoretical basis for clinical evaluation and diagnosis of DACD. Materials and methodsWe characterized Aβ metabolism in the central and peripheral tissues of Zucker diabetic fatty (ZDF) rats with DACD, and then explored the preventive and therapeutic effects of ZiBu PiYin Recipe (ZBPYR). Specifically, we assessed these animals for the formation, transport, and clearance of Aβ; the morphological structure of the blood-brain barrier (BBB); and the potential correlation between Aβ metabolism and intestinal microorganisms. ResultsZBPYR provided improvements in the structure of the BBB, attenuation of Aβ deposition in the central and peripheral tissues, and a delay in the development of DACD by improving the expression of Aβ production, transport, and clearance related protein in ZDF rats. In addition, ZBPYR improved the diversity and composition of intestinal microorganisms, decreased the abundance of Coprococcus, a bacterium closely related to Aβ production, and up regulate the abundance of Streptococcus, a bacterium closely related to Aβ clearance. ConclusionThe mechanism of ZBPYR ability to ameliorate DACD may be closely related to changes in the intestinal microbiome.

A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer’s Disease

BackgroundAmyloid beta protein (Aβ) is a treatment target in Alzheimer’s Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis.MethodsDouble-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21–23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21.ResultsFrom June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups.ConclusionsPosiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects.Trial registrationNCT02925650 on clinicaltrials.gov (registered on 10-24-2016).

Acute Hyperglycemia Induced by Hyperglycemic Clamp Affects Plasma Amyloid-β in Type 2 Diabetes.

Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer's disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted. The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ1-40 and Aβ1-42 concentrations in individuals with T2D and matched controls. Ten participants with T2D and 11 controls (median age, 69 years; range, 66-72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aβ1-40, Aβ1-42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ1-40 and Aβ1-42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. At baseline, Aβ1-40 and Aβ1-42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ1-40: p = 0.034, Aβ1-42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group. Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ40 and Aβ42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.

The Association of Circulating Glucagon-Like Peptide-1 with Cognitive Functions and Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that is clinically characterized by progressive cognitive decline. Glucagon-like peptide-1 (GLP-1) is a hormone that belongs to the incretin family and is released in response to nutrient intake. It plays a role in maintaining metabolic homeostasis and has been suggested to be involved in maintaining the brain microenvironment. However, the role of GLP-1 in AD pathogenesis has not been fully illustrated. This study aims to investigate the clinical relevance of GLP-1 in AD and the effects of GLP-1 in amyloid-β (Aβ) metabolism in vitro. In this study, 39 AD patients and 120 cognitively intact controls were included. Plasma levels of GLP-1 were measured using ELISA. SH-SY5Y cells overexpressing human amyloid precursor protein (APP) were treated with GLP-1. Western blot analysis was used to assess the effects of GLP-1 on the metabolism of Aβ. Plasma GLP-1 levels were decreased with aging. Plasma GLP-1 levels were lower in AD patients in comparison with healthy older adults. Plasma GLP-1 levels were positively associated with Mini-Mental State Examination scores but negatively associated with plasma pTau181 levels. GLP-1 dose-dependently increased the area fraction of mitochondrial staining in vitro. Furthermore, GLP-1 dose-dependently promoted the α-cleavage of APP, thus reducing the generation of Aβ. GLP-1 has neuroprotective effects in AD, and therefore the decrease in GLP-1 levels during aging might contribute to the development of AD.

Monocytes release cystatin F dimer to associate with Aβ and aggravate amyloid pathology and cognitive deficits in Alzheimer’s disease

BackgroundUnderstanding the molecular mechanisms of Alzheimer’s disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aβ) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aβ clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aβ by monocytes in AD remains unclear.MethodsInitially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aβ by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aβ. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology.ResultsOur results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aβ deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aβ by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aβ to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aβ. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice.ConclusionsOur findings highlight that the cystatin F dimer plays a crucial role in regulating Aβ metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention.

Role and application of CRISPR-Cas9 in the management of Alzheimer's disease.

Alzheimer's disease (AD) is a serious health issue that has a significant social and economic impact worldwide. One of the key aetiological signs of the disease is a gradual reduction in cognitive function and irreversible neuronal death. According to a 2019 global report, more than 5.8 million people in the United States (USA) alone have received an AD diagnosis, with 45% of those people falling into the 75-84 years age range. According to the predictions, there will be 15 million affected people in the USA by 2050 due to the disease's steadily rising patient population. Cognitive function and memory formation steadily decline as a result of an irreversible neuron loss in AD, a chronic neurodegenerative illness. Amyloid-beta and phosphorylated Tau are produced and accumulate in large amounts, and glial cells are overactive. Additionally, weakened neurotrophin signalling and decreased synapse function are crucial aspects of AD. Memory loss, apathy, depression, and irritability are among the primary symptoms. The aetiology, pathophysiology, and causes of both cognitive decline and synaptic dysfunction are poorly understood despite extensive investigation. CRISPR/Cas9 is a promising gene-editing technique since it can fix certain gene sequences and has a lot of potential for treating AD and other human disorders. Regardless of hereditary considerations, an altered Aβ metabolism is frequently seen in familial and sporadic AD. Therefore, since mutations in the PSEN-1, PSEN-2 and APP genes are a contributing factor to familial AD, CRISPR/Cas9 technology could address excessive Aβ production or mutations in these genes. Overall, the potential of CRISPR-Cas9 technology outweighs it as currently the greatest gene-editing tool available for researching neurodegenerative diseases like AD.

Modelling Alzheimer's disease in a dish: dissecting amyloid-β metabolism in human neurons.

This scientific commentary refers to 'Inhibition of insulin-degrading enzyme in human neurons promotes amyloid-β deposition' by Rowland et al. (https://doi.org/10.1042/NS20230016). Insulin-degrading enzyme (IDE) and neprilysin (NEP) have been proposed as two Aβ-degrading enzymes supported by human genetics and in vivo data. Rowland et al. provide complementary evidence of a key role for IDE in Aβ metabolism in human-induced pluripotent stem cell (iPSC)-derived cortical neurons.

Distinct effects of cholesterol profile components on amyloid and vascular burdens

AbstractBackgroundCholesterol plays important roles in β‐amyloid (Aβ) metabolism and atherosclerosis. However, the relationships of plasma cholesterol levels with Aβ and cerebral small vessel disease (CSVD) burdens are not fully understood in Asians. Herein, we investigated the relationships between plasma cholesterol profile components and Aβ and CSVD burdens in a large, non‐demented Korean cohort.MethodWe enrolled 1,175 non‐demented participants (456 with unimpaired cognition [CU] and 719 with mild cognitive impairment [MCI]) aged ≥ 45 years who underwent Aβ PET at the Samsung Medical Center in Korea. We performed linear regression analyses with each cholesterol (low‐density lipoprotein cholesterol [LDL‐c], high‐density lipoprotein cholesterol [HDL‐c], and triglyceride) level as a predictor and each image marker (Aβ uptake on PET, white matter hyperintensity [WMH] volume, and hippocampal volume) as an outcome after controlling for potential confounders.ResultIncreased LDL‐c levels (β = 0.014 to 0.115, p = 0.013) were associated with greater Aβ uptake, independent of the APOE e4 allele genotype and lipid‐lowering medication. Decreased HDL‐c levels (β = −0.133 to −0.006, p = 0.032) were predictive of higher WMH volumes. Increased LDL‐c levels were also associated with decreased hippocampal volume (direct effect β = −0.053, p = 0.040), which was partially mediated by Aβ uptake (indirect effect β = −0.018, p = 0.006).ConclusionOur findings highlight that increased LDL‐c and decreased HDL‐c levels are important risk factors for Aβ and CSVD burdens, respectively. Furthermore, considering that plasma cholesterol profile components are potentially modified by diet, exercise, and pharmacological agents, our results provide evidence that regulating LDL‐c and HDL‐c levels is a potential strategy to prevent dementia.

ApoE Mimic Peptide COG1410 Reduces Aβ Deposition and Improves Cognitive Function by Inducing the Transformation of A1/A2 Reactive Astrocytes and Increasing the BDNF Concentration in Brain of APP/PS1 Double Transgenic Mice

The main clinical manifestation of Alzheimer's disease is progressive cognitive decline, and its pathological features are β-amyloid (Aβ) deposition, neurofibrillary tangles, synaptic dysfunction and neuron death. Neuroinflammation is an important reason for the occurrence and development of AD, which is mainly manifested by the accumulation of activated microglia and reactive astrocytes. Apolipoprotein E (ApoE) is one of the most important apolipoprotein in the brain, which is related to metabolism, aggregation and toxicity of Aβ. However, the underlying mechanism needs to be further explored. In this study, we studied the effect of ApoE mimetic peptide COG1410 on spatial learning and memory functions, deposition of Aβ in the dentate gyrus (DG) of APP/PS1 transgenic mice, and the different effects of A1 and A2 subtypes of reactive astrocytes. Administration of COG1410 effectively improved performance in spatial learning and memory of APP/PS1 mice, reduced Aβ deposition and significantly reverted the ratio of A1/A2 reactive astrocytes, which could be associated with BDNF/TrkB signaling pathway. On the whole, the present findings suggest new possibility of using apolipoprotein E mimetic peptide to treat AD with potential effectiveness.

Distinct effects of cholesterol profile components on amyloid and vascular burdens

BackgroundCholesterol plays important roles in β-amyloid (Aβ) metabolism and atherosclerosis. However, the relationships of plasma cholesterol levels with Aβ and cerebral small vessel disease (CSVD) burdens are not fully understood in Asians. Herein, we investigated the relationships between plasma cholesterol profile components and Aβ and CSVD burdens in a large, non-demented Korean cohort.MethodsWe enrolled 1,175 non-demented participants (456 with unimpaired cognition [CU] and 719 with mild cognitive impairment [MCI]) aged ≥ 45 years who underwent Aβ PET at the Samsung Medical Center in Korea. We performed linear regression analyses with each cholesterol (low-density lipoprotein cholesterol [LDL-c], high-density lipoprotein cholesterol [HDL-c], and triglyceride) level as a predictor and each image marker (Aβ uptake on PET, white matter hyperintensity [WMH] volume, and hippocampal volume) as an outcome after controlling for potential confounders.ResultsIncreased LDL-c levels (β = 0.014 to 0.115, p = 0.013) were associated with greater Aβ uptake, independent of the APOE e4 allele genotype and lipid-lowering medication. Decreased HDL-c levels (β = − 0.133 to − 0.006, p = 0.032) were predictive of higher WMH volumes. Increased LDL-c levels were also associated with decreased hippocampal volume (direct effect β = − 0.053, p = 0.040), which was partially mediated by Aβ uptake (indirect effect β = − 0.018, p = 0.006).ConclusionsOur findings highlight that increased LDL-c and decreased HDL-c levels are important risk factors for Aβ and CSVD burdens, respectively. Furthermore, considering that plasma cholesterol profile components are potentially modified by diet, exercise, and pharmacological agents, our results provide evidence that regulating LDL-c and HDL-c levels is a potential strategy to prevent dementia.

Circular RNAs in Alzheimer's Disease: A New Perspective of Diagnostic and Therapeutic Targets.

Circular RNAs (circRNAs), as covalently closed single-stranded noncoding RNA molecules, have been recently identified to involve in several biological processes, principally through targeting microRNAs. Among various neurodegenerative diseases (NDs), accumulating evidence has proposed key roles for circRNAs in the pathogenesis of Alzheimer's disease (AD); although the exact relationship between these RNA molecules and AD progression is not clear, they have been believed to mostly act as miRNA sponges or gene transcription modulators through correlating with multiple proteins, involved in the accumulation of Amyloid β (Aβ) peptides, as well as tau protein, as AD's pathological hallmark. More interestingly, circRNAs have also been reported to play diagnostic and therapeutic roles during AD progression. Literature review indicated that circRNAs could essentially contribute to the onset and development of AD. Thus, in the current review, the circRNAs' biogenesis and functions are addressed at first, and then the interplay between particular circRNAs and AD is comprehensively discussed. Eventually, the diagnostic and therapeutic significance of these noncoding RNAs is highlighted in brief. A large number of circRNAs are expressed in the brain. Thereby, these RNA molecules are noticed as potential regulators of neural functions in healthy circumstances, as well as neurological disorders. Moreover, circRNAs have also been reported to have potential diagnostic and therapeutic capacities in relation to AD, the most prevalent ND. CircRNAs have been shown to act as sponges for miRNAs, thereby regulating the function of related miRNAs, including oxidative stress, reduction of neuroinflammation, and the formation and metabolism of Aβ, all of which developed in AD. CircRNAs have also been proposed as biomarkers that have potential diagnostic capacities in AD. Despite these characteristics, the use of circRNAs as therapeutic targets and promising diagnostic biomarkers will require further investigation and characterization of the function of these RNA molecules in AD.

Acute inhibition of AMPA receptors by perampanel reduces amyloid β-protein levels by suppressing β-cleavage of APP in Alzheimer's disease models.

Hippocampal hyperexcitability is a promising therapeutic target to prevent Aβ deposition in AD since enhanced neuronal activity promotes presynaptic Aβ production and release. This article highlights the potential application of perampanel (PER), an AMPA receptor (AMPAR) antagonist approved for partial seizures, as a therapeutic agent for AD. Using transgenic AD mice combined with invivo brain microdialysis and primary neurons under oligomeric Aβ-evoked neuronal hyperexcitability, the acute effects of PER on Aβ metabolism were investigated. A single oral administration of PER rapidly decreased ISF Aβ40 and Aβ42 levels in the hippocampus of J20, APP transgenic mice, without affecting the Aβ40 /Aβ42 ratio; 5 mg/kg PER resulted in declines of 20% and 31%, respectively. Moreover, PER-treated J20 manifested a marked decrease in hippocampal APP βCTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPPβ levels, a direct byproduct of β-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric Aβ-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF Aβ clearance, a γ-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF Aβ, indicating that the acute effect of PER is predominantly on Aβ production. In conclusion, acute treatment of PER reduces Aβ production by suppressing β-cleavage of amyloid-β precursor protein effectively, indicating a potential effect of PER against Aβ pathology in AD.

A new perspective on Alzheimer's disease: microRNAs and circular RNAs.

microRNAs (miRNAs) play a multifaceted role in the pathogenesis of Alzheimer's disease (AD). miRNAs regulate several aspects of the disease, such as Aβ metabolism, tau phosphorylation, neuroinflammation, and synaptic function. The dynamic interaction between miRNAs and their target genes depends upon various factors, including the subcellular localization of miRNAs, the relative abundance of miRNAs and target mRNAs, and the affinity of miRNA-mRNA interactions. The miRNAs are released into extracellular fluids and subsequently conveyed to specific target cells through various modes of transportation, such as exosomes. In comparison, circular RNAs (circRNAs) are non-coding RNA (ncRNA) characterized by their covalently closed continuous loops. In contrast to linear RNA, RNA molecules are circularized by forming covalent bonds between the 3'and 5'ends. CircRNA regulates gene expression through interaction with miRNAs at either the transcriptional or post-transcriptional level, even though their precise functions and mechanisms of gene regulation remain to be elucidated. The current stage of research on miRNA expression profiles for diagnostic purposes in complex disorders such as Alzheimer's disease is still in its early phase, primarily due to the intricate nature of the underlying pathological causes, which encompass a diverse range of pathways and targets. Hence, this review comprehensively addressed the alteration of miRNA expression across diverse sources such as peripheral blood, exosome, cerebrospinal fluid, and brain in AD patients. This review also addresses the nascent involvement of circRNAs in the pathogenesis of AD and their prospective utility as biomarkers and therapeutic targets for these conditions in future research.

Therapeutic Implications of Renin-Angiotensin System Modulators in Alzheimer's Dementia.

The Renin-Angiotensin System (RAS) has attracted considerable interest beyond its traditional cardiovascular role due to emerging data indicating its potential involvement in neurodegenerative diseases, including Alzheimer's dementia (AD). This review investigates the therapeutic implications of RAS modulators, specifically focusing on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and renin inhibitors in AD. ACEIs, commonly used for hypertension, show promise in AD by reducing angiotensin (Ang) II levels. This reduction is significant as Ang II contributes to neuroinflammation, oxidative stress, and β-amyloid (Aβ) accumulation, all implicated in AD pathogenesis. ARBs, known for vasodilation, exhibit neuroprotection by blocking Ang II receptors, improving cerebral blood flow and cognitive decline in AD models. Renin inhibitors offer a novel approach by targeting the initial RAS step, displaying anti-inflammatory and antioxidant effects that mitigate AD degeneration. Preclinical studies demonstrate RAS regulation's favorable impact on neuroinflammation, neuronal damage, cognitive function, and Aβ metabolism. Clinical trials on RAS modulators in AD are limited, but with promising results, ARBs being more effective that ACEIs in reducing cognitive decline. The varied roles of ACEIs, ARBs, and renin inhibitors in RAS modulation present a promising avenue for AD therapeutic intervention, requiring further research to potentially transform AD treatment strategies.

Folate Deficiency Increased Microglial Amyloid-β Phagocytosis via the RAGE Receptor in Chronic Unpredictable Mild-Stress Rat and BV2 Cells.

Depression is often considered one of the prevalent neuropsychiatric symptoms of Alzheimer's disease (AD). β-amyloid (Aβ) metabolism disorders and impaired microglia phagocytosis are potential pathological mechanisms between depression and AD. Folate deficiency (FD) is a risk factor for depression and AD. In this study, we used a chronic unpredictable mild stress (CUMS) rat model and a model of Aβ phagocytosis by BV2 cells to explore the potential mechanisms by which FD affects depression and AD. The results revealed that FD exacerbated depressive behavior and activated microglia in CUMS rats, leading to an increase in intracellular Aβ and phagocytosis-related receptors for advanced glycation end products (RAGE). Then, in vitro results showed that the expression of the RAGE receptor and M2 phenotype marker (CD206) were upregulated by FD treatment in BV2 cells, leading to an increase in Aβ phagocytosis. However, there was no significant difference in the expression of toll-like receptor 4 (TLR4) and clathrin heavy chain (CHC). Furthermore, when using the RAGE-specific inhibitor FPS-ZM1, there was no significant difference in Aβ uptake between folate-normal (FN) and FD BV2 cell groups. In conclusion, these findings suggest FD may promote microglia phagocytosis Aβ via regulating the expression of RAGE or microglia phenotype under Aβ treatment.

Hepatic soluble epoxide hydrolase activity regulates cerebral Aβ metabolism and the pathogenesis of Alzheimer’s disease in mice

Alzheimer's disease (AD) is caused by a complex interaction between genetic and environmental factors. However, how the role of peripheral organ changes in response to environmental stimuli during aging in AD pathogenesis remains unknown. Hepatic soluble epoxide hydrolase (sEH) activity increases with age. Hepatic sEH manipulation bidirectionally attenuates brain amyloid-β (Aβ) burden, tauopathy, and cognitive deficits in AD mouse models. Moreover, hepatic sEH manipulation bidirectionally regulates the plasma level of 14,15-epoxyeicosatrienoic acid (-EET), which rapidly crosses the blood-brain barrier and modulates brain Aβ metabolism through multiple pathways. A balance between the brain levels of 14,15-EET and Aβ is essential for preventing Aβ deposition. In AD models, 14,15-EET infusion mimicked the neuroprotective effects of hepaticsEH ablation at biological and behavioral levels. These results highlight the liver's key role in AD pathology,and targeting the liver-brain axis in response to environmental stimuli may constitute a promising therapeutic approach for AD prevention.

MicroRNA-125a-3p Modulate Amyloid β-Protein through the MAPK Pathway in Alzheimer's Disease.

MicroRNA (miR)-125a-3p is reported to play an important role in some central nervous system diseases, such as Alzheimer's disease (AD). However, a study has not been conducted on the mechanism of miR-125a-3p in the pathological process of AD. First, we assessed the expression of miR-125a-3p in AD cohort. Subsequently, we altered the expressions of miR-125a-3p to assess its role in cell viability, cell apoptosis, amyloid-β (Aβ) metabolism, and synaptic activity. Finally, we identified its potential mechanism underlying AD pathology. This study unveiled the potential function of miR-125a-3p through modulating amyloid precursor protein processing. Additionally, miR-125a-3p influenced cell survival and activated synaptic expression through the modulation of Aβ metabolism in the mitogen-activated protein kinase (MAPK) pathway via fibroblast growth factor receptor 2. Our study indicates that targeting miR-125a-3p may be an applicable therapy for AD in the future. However, more in vitro and in vivo studies with more samples are needed to confirm these results.