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Background: Impaired clearance of amyloid-β protein (Aβ) in the peripheral system is a crucial event in the pathogenesis of sporadic Alzheimer's disease (AD). Dysfunctional monocytes with deficient clearance of Aβ and increased secretion of pro-inflammatory factors in the periphery are considered to contribute to AD development. Multiple studies suggest that IL-4 can inhibit the inflammatory response and enhance the expression and activity of cathepsin protease associated with intracellular clearance of Aβ by monocytes. Objective: To investigate the effects of interleukin-4 (IL-4) on Aβ clearance and inflammatory response of monocytes in vitro. Methods: In this study, flow cytometry, confocal microscopy and ELISA techniques were used for measurement of Aβ clearance and its related mechanisms of monocytes. Results: We found that the mean intracellular content and uptake ratios of Aβ42 in total monocytes, as well as in the CD14 + CD16− subset, were enhanced by IL-4, concomitant with the degradation of Aβ42 by monocytes. And IL-4 treatment also increased expression of scavenger receptor CD36 and Macrophage scavenger receptor 1 (MSR1) on monocytes. It was shown that IL-4 increased the Aβ immunoreactive area within lysosomal markers, including early endosome antigen 1 (EEA1), lysosome-associated membrane glycoprotein 1 and 2 (LAMP1 and 2) and Aβ degradative enzymes cathepsin B and S in monocytes, but reduced secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) by monocytes. Conclusions: Our study supports the role of IL-4 in regulating Aβ clearance and inflammatory response by monocytes, suggesting that IL-4 may have therapeutic potential for AD. [ABSTRACT FROM AUTHOR]

Although Alzheimer's disease (AD) is traditionally viewed as a central nervous system disorder driven by the cerebral accumulation of toxic beta-amyloid (Aβ) peptide, new interpretations of the amyloid cascade hypothesis have led to the recognition of the dynamic equilibrium in which Aβ resides and the importance of peripheral Aβ production and degradation in maintaining healthy Aβ levels. Our review sheds light on the critical role of peripheral organs, particularly the liver, in the metabolism and clearance of circulating Aβ. We explore the mechanisms of Aβ transport across the blood–brain barrier (BBB) via transport proteins such as LRP1 and P-glycoprotein. We also examine how peripheral clearance mechanisms, including enzymatic degradation and phagocytic activity, impact Aβ homeostasis. Our review also discusses potential therapeutic strategies targeting peripheral Aβ clearance pathways. By enhancing these pathways, we propose a novel approach to reducing cerebral Aβ burden, potentially slowing AD progression. [ABSTRACT FROM AUTHOR]

Abstract Background Understanding 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. Methods Initially, 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. Results Our 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. Conclusions Our 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.

Background: Understanding 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. Methods: Initially, 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. Results: Our 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. Conclusions: Our 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. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease, the primary cause of dementia, is characterized by neuropathologies, such as amyloid plaques, synaptic and neuronal degeneration, and neurofibrillary tangles. Although amyloid plaques are the primary characteristic of Alzheimer’s disease in the central nervous system and peripheral organs, targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer’s disease treatment. Metabolic abnormalities are commonly observed in patients with Alzheimer’s disease. The liver is the primary peripheral organ involved in amyloid-beta metabolism, playing a crucial role in the pathophysiology of Alzheimer’s disease. Notably, impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer’s disease. In this review, we explore the underlying causes of Alzheimer’s disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism. Furthermore, we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer’s disease.

Background: Abnormal intracellular expression and aggregation of α-synuclein (α-syn) is the histopathological hallmark of several neurodegenerative diseases especially Parkinson's disease. However, safe and efficient approaches to clear α-syn remain unavailable. Objective: This study aimed to investigate the process of peripheral catabolism of brain-derived α-syn. Methods: Thirty patients with atrioventricular reentrant tachycardia (AVRT) (left accessory pathways) who underwent radiofrequency catheter ablation (RFCA) were enrolled in this study. Blood was collected via catheters from superior vena cava (SVC), inferior vena cava (IVC) proximal to the hepatic vein (HV), the right femoral vein (FV), and femoral artery (FA) simultaneously during RFCA. Plasma α-syn levels of AVRT patients and soluble α-syn levels of the brain samples were measured using enzyme-linked immunosorbent assay kits. Results: The α-syn concentrations in different locations of veins were divided by time-matched arterial α-syn concentrations to generate the venous/arterial (V/A) ratio. The V/A ratio of α-syn from the SVC was 1.204 (1.069–1.339, 95% CI), while the V/A ratio of α-syn from IVC was 0.831 (0.734–0.928, 95% CI), suggesting that brain-derived α-syn in the arterial blood was physiologically cleared while going through the peripheral organs and tissues. And it was estimated that about half of brain soluble α-syn could efflux and be cleared in the periphery. Moreover, the glomerular filtration rate was found correlated with V-A difference (FA-ICV) (p = 0.0272). Conclusion: Under physiological conditions, brain-derived α-syn could efflux into and be catabolized by the peripheral system. The kidney may play a potential role in the clearance of α-syn. [ABSTRACT FROM AUTHOR]

[Display omitted] • BP-PEG could promote the accumulation and metabolism of P-Tau in the liver and kidneys. • BP-PEG could improve the symptoms of AD. • BP-PEG appear to be a safe and effective strategy for the peripheral clearance of P-Tau associated with AD. The onset of Alzheimer's disease (AD) is closely related to the accumulation of phosphorylated Tau proteins (P-Tau). However, due to the hindrance posed by the blood–brain barrier (BBB), current therapies targeting brain-derived P-Tau are largely ineffective. Interestingly, the clearance of peripheral P-Tau can eliminate P-Tau from the brain, enabling AD treatment and overcoming the challenges created by the BBB. Here, we prepared polyethylene glycol (PEG)-modified black phosphorus nanosheets (BP-PEG), which showed extended systemic circulation and acted as efficient "garbage trucks" for the removal of peripheral P-Tau. BP-PEG exhibited an exceptional capacity to bind to P-Tau in vitro. Further, in vivo biodistribution analysis demonstrated that BP-PEG accumulated in the liver and kidneys, which are the same organs that metabolize P-Tau. In vivo studies revealed that in okadaic acid (OA)-induced mouse models of AD, BP-PEG significantly reduced the levels of P-Tau in both the peripheral blood and the brain. Moreover, by promoting the clearance of peripheral P-Tau, BP-PEG improved several health indicators in mice, including cognitive function, glucose metabolism in the brain, inflammatory markers in the plasma and hippocampus, oxidative stress, and mitochondrial and myelin morphology. In conclusion, this study provides a new strategy for AD treatment, demonstrating the therapeutic value of removing P-Tau from the peripheral blood, and it also represents a novel attempt for the application of BP-PEG in AD therapy. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive impairments. Amyloid-β (Aβ) deposition and neurotoxicity play important roles in AD. It has been widely reported that heparan sulfate (HS) proteoglycans play a nonnegligible role in the release, uptake and misfolding of Aβ, resulting in the discovery of HS as a therapeutic drug for AD. In this manuscript, HS from porcine mucosa could promote Aβ fibrosis and improve the cognitive defects of APPswe/PS1ΔE9 mice. Furthermore, HS enhanced the phagocytosis of neutrophils to clear Aβ 1 – 42 from peripheral circulation, reduced peripheral Aβ 1 – 42 flow to the brain and increased Aβ efflux from the brain. Therefore, the deposition of Aβ plaques in the brain was decreased. In addition, HS alleviated neutrophil infiltration and reduced neuroinflammation. Conclusively, HS is a promising neuroprotective candidate for AD treatment. [Display omitted] [ABSTRACT FROM AUTHOR]