Peripheral Aβ Research Articles

Pathology of Amyloid-β (Aβ) Peptide Peripheral Clearance in Alzheimer's Disease.

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.

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.

Hepatic LRP-1 plays an important role in amyloidosis in Alzheimer's disease mice: Potential role in chronic heavy alcohol feeding

BackgroundHepatic lipoprotein receptor-related protein 1 (LRP-1) plays a central role in peripheral amyloid beta (Aβ) clearance, but its importance in Alzheimer's disease (AD) pathology is understudied. Our previous work showed that intragastric alcohol feeding to C57BL/6 J mice reduced hepatic LRP-1 expression which correlated with significant AD-relevant brain changes. Herein, we examined the role of hepatic LRP-1 in AD pathogenesis in APP/PS1 AD mice using two approaches to modulate hepatic LRP-1, intragastric alcohol feeding to model chronic heavy drinking shown by us to reduce hepatic LRP-1, and hepato-specific LRP-1 silencing. MethodsEight-month-old male APP/PS1 mice were fed ethanol or control diet intragastrically for 5 weeks (n = 7–11/group). Brain and liver Aβ were assessed using immunoassays. Three important mechanisms of brain amyloidosis were investigated: hepatic LRP-1 (major peripheral Aβ regulator), blood-brain barrier (BBB) function (vascular Aβ regulator), and microglia (major brain Aβ regulator) using immunoassays. Spatial LRP-1 gene expression in the periportal versus pericentral hepatic regions was confirmed using NanoString GeoMx Digital Spatial Profiler. Further, hepatic LRP-1 was silenced by injecting LRP-1 microRNA delivered by the adeno-associated virus 8 (AAV8) and the hepato-specific thyroxine-binding globulin (TBG) promoter to 4-month-old male APP/PS1 mice (n = 6). Control male APP/PS1 mice received control AAV8 (n = 6). Spatial memory and locomotion were assessed 12 weeks after LRP-1 silencing using Y-maze and open-field test, respectively, and brain and liver Aβ were measured. ResultsAlcohol feeding reduced plaque-associated microglia in APP/PS1 mice brains and increased aggregated Aβ (p < 0.05) by ELISA and 6E10-positive Aβ load by immunostaining (p < 0.05). Increased brain Aβ corresponded with a significant downregulation of hepatic LRP-1 (p < 0.01) at the protein and transcript level, primarily in pericentral hepatocytes (zone 3) where alcohol-induced injury occurs. Hepato-specific LRP-1 silencing significantly increased brain Aβ and locomotion hyperactivity (p < 0.05) in APP/PS1 mice. ConclusionChronic heavy alcohol intake reduced hepatic LRP-1 expression and increased brain Aβ. The hepato-specific LRP-1 silencing similarly increased brain Aβ which was associated with behavioral deficits in APP/PS1 mice. Collectively, our results suggest that hepatic LRP-1 is a key regulator of brain amyloidosis in alcohol-dependent AD.

Peripheral amyloid-β clearance mediates cognitive impairment in non-alcoholic fatty liver disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a prevalent risk factor for cognitive impairment. Cerebral amyloid-β (Aβ) accumulation, as an important pathology of cognitive impairment, can be caused by impaired Aβ clearance in the periphery. The liver is the primary organ for peripheral Aβ clearance, but the role of peripheral Aβ clearance in NAFLD-induced cognitive impairment remains unclear. MethodsWe examined correlations between NAFLD severity, Aβ accumulation, and cognitive performance in female Sprague-Dawley rats. The impact of NAFLD on hepatic Aβ clearance and the involvement of low-density lipoprotein receptor-related protein 1 (LRP-1) were assessed in rat livers and cultured hepatocytes. Additionally, a case-control study, including 549 NAFLD cases and 549 controls (782 males, 316 females), investigated the interaction between NAFLD and LRP-1 rs1799986 polymorphism on plasma Aβ levels. FindingsThe severity of hepatic steatosis and dysfunction closely correlated with plasma and cerebral Aβ accumulations and cognitive deficits in rats. The rats with NAFLD manifested diminished levels of LRP-1 and Aβ in liver tissue, with these reductions inversely proportional to plasma and cerebral Aβ concentrations and cognitive performance. In vitro, exposure of HepG2 cells to palmitic acid inhibited LRP-1 expression and Aβ uptake, which was subsequently reversed by a peroxisome proliferator-activated receptor α (PPARα) agonist. The case-control study revealed NAFLD to be associated with an increment of 8.24% and 10.51% in plasma Aβ40 and Aβ42 levels, respectively (both P <0.0001). Moreover, the positive associations between NAFLD and plasma Aβ40 and Aβ42 levels were modified by the LRP-1 rs1799986 polymorphism (P for interaction = 0.0017 and 0.0015, respectively). InterpretationLRP-1 mediates the adverse effect of NAFLD on peripheral Aβ clearance, thereby contributing to cerebral Aβ accumulation and cognitive impairment in NAFLD. FundingMajor International (Regional) Joint Research Project, National Key Research and Development Program of China, National Natural Science Foundation of China, and the Angel Nutrition Research Fund.

Abstract WP291: Cerebral Amyloid Angiopathy Induces Liver Inflammation in Aged Mice

Introduction: Cerebral amyloid angiopathy (CAA) is a chronic age-related neurodegenerative disease, identified by the presence of amyloid-beta (Aβ) deposition within the vasculature of the brain, leading to stroke and progressive cognitive decline. The liver is a key peripheral organ involved in the clearance of excess Aβ in the circulation. However, the role of the brain-liver axis in CAA is unknown. Here, we investigate inflammatory changes in the liver in a murine model of CAA. Methods: Aged (&gt;23 months) male and female Tg-SwDI (CAA) mice harboring Swedish, Dutch, and Iowa mutations of the human amyloid precursor protein were used as a mouse model of CAA along with age-matched wild-type (WT) controls (n=3-7/grp). Hepatic inflammation was analyzed with histological and immunofluorescence imaging. Single cells from liver tissue were isolated and analyzed using flow cytometry. Total RNA was isolated to examine gene expression in the liver using real-time quantitative PCR. Results: Our data showed that CAA increases infiltration of immune cells proximal to liver sinusoids across both sexes compared to WT mice. We found increased macrophages (i.e., F4/80 + cells) in the liver of CAA mice compared to WT controls. Flow cytometry on the liver revealed that female CAA mice had a significant increase in dendritic cells (i.e., CD80 + CD45 + CD11c + cells, *** P &lt;0.001) compared to WT females. Further, we found that Oatp2 , a membrane transporter which mediates hepatocytic uptake of toxic molecules (e.g., Aβ), is associated with sex-specific CAA pathophysiology in the liver. Conclusions: In this study, we found that sex differences may exist in CAA-induced liver inflammation. Further investigations are needed to study how vascular amyloidosis shapes the immune responses and peripheral Aβ clearance in the context of aging and CAA.

Nasal delivery of polymeric nanoDisc mobilizes a synergy of central and peripheral amyloid-β clearance to treat Alzheimer's disease.

The disequilibrium of amyloid β-peptide (Aβ) between the central and peripheral pools has been claimed as an initiating event in Alzheimer's disease (AD). In this study, we employ discoidal high-density lipoproteins (HDL-Disc) mimicking Aβ antibody for directional flux of Aβ from central to peripheral catabolism, with desirable safety and translation potential. Structurally, HDL-Disc assembly (polyDisc) is prepared with aid of chitosan derivative polymerization. After intranasal administration and response to slightly acidic nasal microenvironment, polyDisc depolymerizes into carrier-free HDL-Disc with chitosan derivatives that adhere to the mucosal layer to reversibly open tight junctions, helping HDL-Disc penetrate the olfactory pathway into brain. Thereafter, HDL-Disc captures Aβ into microglia for central clearance or ferries Aβ out of the brain for liver-mediated compensatory catabolism. For synergy therapy, intranasal administration of polyDisc can effectively reduce intracerebral Aβ burden by 97.3% and vascular Aβ burden by 73.5%, ameliorate neurologic damage, and rescue memory deficits in APPswe/PS1dE9 transgenic AD mice with improved safety, especially vascular safety. Collectively, this design provides a proof of concept for developing Aβ antibody mimics to mobilize a synergy of central and peripheral Aβ clearance for AD treatment.

Amyloid‐β and monocytes in Alzheimer’s disease

AbstractBackgroundCompelling evidence suggests that failure of Aβ clearance is a major mechanism of late‐onset Alzheimer’s disease (LOAD). The molecular basis remains unclear, but genome‐wide association studies (GWAS) strongly point to altered phagocytosis/endocytosis in the CNS and peripheral. Previously, we have demonstrated perturbation of monocyte basal and stimulated innate phagocytosis in LOAD.MethodFlow cytometry immunophenotyping (FCIP) is used to investigate the relationship between peripheral blood leukocyte transport Aβ and disease stage in AD patients.ResultsIn this study, we identified a subset of circulating intermediate monocytes (CD14+CD16+) that carry high amounts of Aβ dimers and co‐express the cell migration receptors CX3CR1 and CCR2. We then performed a quantitative study involving 165 AIBL participants and found that the number of monocytes carrying Aβ was decreased by 26% in AD and was inversely correlated with the subjects’ brain Aβ load and accumulation rate. Curiously, our further investigations revealed that the predominant type of infiltrating monocytes in human CSF are intermediate monocytes (CD45+CD14+CD16+).ConclusionThe passage of those cells across blood‐brain barrier and their physiological significance are unknown. But it suggests a possible mechanism for the transport of brain Aβ to the periphery by monocytes.

Targeting Alzheimer's Disease: The Critical Crosstalk between the Liver and Brain.

Alzheimer’s disease (AD), an age-related neurodegenerative disorder, is currently incurable. Imbalanced amyloid-beta (Aβ) generation and clearance are thought to play a pivotal role in the pathogenesis of AD. Historically, strategies targeting Aβ clearance have typically focused on central clearance, but with limited clinical success. Recently, the contribution of peripheral systems, particularly the liver, to Aβ clearance has sparked an increased interest. In addition, AD presents pathological features similar to those of metabolic syndrome, and the critical involvement of brain energy metabolic disturbances in this disease has been recognized. More importantly, the liver may be a key regulator in these abnormalities, far beyond our past understanding. Here, we review recent animal and clinical findings indicating that liver dysfunction represents an early event in AD pathophysiology. We further propose that compromised peripheral Aβ clearance by the liver and aberrant hepatic physiological processes may contribute to AD neurodegeneration. The role of a hepatic synthesis product, fibroblast growth factor 21 (FGF21), in the management of AD is also discussed. A deeper understanding of the communication between the liver and brain may lead to new opportunities for the early diagnosis and treatment of AD.

Erythropoietin signaling in peripheral macrophages is required for systemic β-amyloid clearance.

Impaired clearance of beta-amyloid (Aβ) is a primary cause of sporadic Alzheimer's disease (AD). Aβ clearance in the periphery contributes to reducing brain Aβ levels and preventing Alzheimer's disease pathogenesis. We show here that erythropoietin (EPO) increases phagocytic activity, levels of Aβ-degrading enzymes, and Aβ clearance in peripheral macrophages via PPARγ. Erythropoietin is also shown to suppress Aβ-induced inflammatory responses. Deletion of EPO receptor in peripheral macrophages leads to increased peripheral and brain Aβ levels and exacerbates Alzheimer's-associated brain pathologies and behavioral deficits in AD-model mice. Moreover, erythropoietin signaling is impaired in peripheral macrophages of old AD-model mice. Exogenous erythropoietin normalizes impaired EPO signaling and dysregulated functions of peripheral macrophages in old AD-model mice, promotes systemic Aβ clearance, and alleviates disease progression. Erythropoietin treatment may represent a potential therapeutic approach for Alzheimer's disease.

Peripheral Immune Cells and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.

Inflammation plays a role in occurrence and progression of Alzheimer's disease (AD). Whether peripheral immune cells are involved in major pathological processes including amyloid-β plaques and tau tangles is still controversial. We aimed to examine whether peripheral immune cells counts were associated with early changes in cerebrospinal fluid (CSF) biomarkers of AD pathology in cognitively intact older adults. This study included 738 objective cognitive normal participants from the Chinese Alzheimer's Biomarker and Lifestyle (CABLE) database. Group comparisons of peripheral immune cells counts were tested by analysis of covariance. Multiple linear regression models were used to examine the associations of peripheral immune cells counts with CSF AD biomarkers. In preclinical AD, peripheral lymphocytes and eosinophils changed dynamically along with disease progression. Consistently, regression analysis showed that lymphocytes and eosinophils were associated with Aβ pathology. There were no interaction effects of peripheral immune cells counts with APOE ɛ4, gender, age, and educate. Eosinophil to lymphocyte ratio were also significantly associated with Aβ-related biomarkers. Our findings showed the relationship between peripheral immune cells and Aβ pathological biomarkers, which indicated that peripheral immune might play a role in progression of AD pathology.

Effects of heparan sulfate from porcine mucosa on Aβ1–42-induced neurotoxicity in vitro and in vivo

Amyloid-β (Aβ) deposition and neurotoxicity play an important role in Alzheimer's disease (AD). Notably, the nonnegligible role of endogenous heparan sulfate (HS) in the release, uptake and misfolding of Aβ sheds light on the discovery of HS as an effective drug for AD. In this work, the effects of HS from porcine mucosa (PMHS) on Aβ1–42-induced neurotoxicity were investigated both in vitro and in vivo. The in vitro AD model was established in SH-SY5Y via treatment with oligomeric Aβ1–42, and the in vivo AD model was established by intracerebroventricular injection of Aβ1–42 to KM mice. The results showed that in vitro, PMHS could ameliorate the inflammation and apoptosis response of SH-SY5Y cells induced by Aβ1–42; in vivo, PMHS could not only improve the cognitive impairment induced by Aβ1–42 but also inhibit neuroinflammation and apoptosis in the brain. Furthermore, PMHS lowered the levels of Aβ1–42 in the peripheral circulation and brain by improving the phagocytosis function of neutrophils. This is the first report that PMHS enhances the phagocytosis function of neutrophils to alleviate Aβ-induced neurotoxicity. Moreover, our work verified the feasibility of peripheral Aβ clearance for improving neurotoxicity. Conclusively, we believe that PMHS could be developed into neuroprotective drugs for AD.

Peripheral Aβ acts as a negative modulator of insulin secretion

Type 2 diabetes mellitus is known to be a risk factor for Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. In AD, the cerebral accumulation of amyloid β (Aβ) triggers a pathological cascade leading to neurodegeneration. Plasma Aβ levels are thought to reflect the brain amyloid pathology and currently used as a diagnostic biomarker of AD. However, amyloid precursor protein and Aβ-generating enzymes, β- and γ-secretases, are widely expressed in various peripheral tissues. Previous reports have shown that glucose and insulin loading cause a transient increase of plasma Aβ in mice and humans. These findings led us to speculate that plasma Aβ is produced from glucose- and insulin-susceptible peripheral tissues to play a role in glucose and insulin metabolism. To test this hypothesis, we investigated the effects of glucose and insulin on Aβ secretion and the effect of Aβ on insulin secretion in vivo, ex vivo, and in vitro. Aβ was found to be secreted from β-cells of the pancreas along with insulin upon glucose stimulation. Upon insulin stimulation, Aβ was secreted from cells of insulin-targeted organs, such as adipose tissues, skeletal muscles, and the liver, along with their organokines. Furthermore, Aβ inhibited the glucose-triggered insulin secretion from β-cells, slowing down glucose clearance from the blood. These results suggest that peripheral Aβ acts as a negative modulator of insulin secretion. Our findings provide a possible mechanism linking diabetes to AD and call attention to how plasma Aβ levels are used in AD diagnosis.

The Role of Circulating Aβ Seeds in the Progression of Cerebral Amyloidosis.

While understudied, it is suspected that peripheral Aβ peptides affect Alzheimer’s disease (AD)-associated pathological changes in the brain. The peripheral sink hypothesis postulates that the central and peripheral pools of Aβ co-exist in equilibrium. As such, cerebral amyloid levels may be modulated by intervening circulating Aβ. In this commentary, we discuss relevant literature supporting the potential role of peripheral Aβ in exacerbating brain amyloidosis in both humans and mouse models of AD. Moreover, we highlight the need to further understand the mechanisms by which circulating Aβ peptides may reach the brain and contribute to neuropathology. Finally, we discuss the implications of targeting peripheral Aβ as a therapeutic approach in treating AD.

Recent advancements toward non-invasive imaging of retinal amyloid-beta for early detection of Alzheimer's disease.

Recent advancements toward non-invasive imaging of retinal amyloid-beta for early detection of Alzheimer's disease.

Dual-targeted magnetic mesoporous silica nanoparticles reduce brain amyloid-β burden via depolymerization and intestinal metabolism.

Rationale: Active removal of excess peripheral amyloid-β (Aβ) can potentially treat Alzheimer's disease (AD). However, the peripheral clearance of Aβ using an anti-Aβ monoclonal antibody (mAb) cannot remove PET-detectable Aβ within the brain. This may be due to the inability of mAb to cross the blood-brain barrier (BBB) to degrade insoluble brain Aβ plaques and block liver dysfunction.Methods: We developed a dual-targeted magnetic mesoporous silica nanoparticle (HA-MMSN-1F12) through surface-coupled Aβ42-targeting antibody 1F12 and CD44-targeting ligand hyaluronic acid (HA).Results: HA-MMSN-1F12 had a high binding affinity toward Aβ42 oligomers (Kd = 1.27 ± 0.34 nM) and revealed robust degradation of Aβ42 aggregates. After intravenous administration of HA-MMSN-1F12 into ten-month-old APP/PS1 mice for three weeks (4 mg/kg/week), HA-MMSN-1F12 could cross the BBB and depolymerize brain Aβ plaques into soluble Aβ species. In addition, it also avoided hepatic uptake and excreted captured Aβ species through intestinal metabolism, thereby reducing brain Aβ load and neuroinflammation and improving memory deficits of APP/PS1 mice. Furthermore, the biochemical analysis showed that HA-MMSN-1F12 did not detect any toxic side effects on the liver and kidney. Thus, the efficacy of HA-MMSN-1F12 is associated with the targeted degradation of insoluble brain Aβ plaques, avoidance of non-specific hepatic uptake, and excretion of peripheral Aβ through intestinal metabolism.Conclusions: The study provides a new avenue for treating brain diseases by excreting disease-causing biohazards using intestinal metabolism.

Recent advances in blood and gut microbiota biomarkers for Alzheimer&amp;rsquo;s disease

<p indent="0mm">Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases, with a high prevalence among the elderly. However, the mechanism of its occurrence is not clear, and there is a lack of convenient means of early diagnosis, which makes it difficult to intervene in and treat the disease in its early stage. In recent years, with the development of mass spectrometry, immunological methods and other new technologies, potential biomarkers for early diagnosis and disease monitoring of Alzheimer’s disease have been identified, including peripheral blood Aβ, p-tau, exosomes, miRNA, and intestinal bacteria. In this article, we reviewed the current research status of AD peripheral blood biomarkers and AD-related intestinal microbiota biomarkers, in order to provide a reference for the early diagnosis and prediction of the disease progression.

Blood Triglyceride and High-Density Lipoprotein Levels Are Associated with Plasma Amyloid-β Transport: A Population-Based Cross-Sectional Study.

Studies have found that blood lipids are associated with plasma amyloid-β (Aβ) levels, but the underlying mechanism is still unclear. Two Aβ transporters, soluble form of low-density lipoprotein receptor related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE), are crucial in peripheral Aβ transport. The aim was to investigate the effects of lipids on the relationships between plasma Aβ and transporter levels. This study included 1,436 adults aged 40 to 88 years old. Blood Aβ, sLRP1, sRAGE, and lipid levels were measured. Univariate and multivariate analyses were used to analyze the relationships between lipids and plasma Aβ, sLRP1, and sRAGE. After adjusting for all possible covariates, high-density lipoprotein (HDL-c) was positively associated with plasma Aβ42 and sRAGE (β= 6.158, p = 0.049; β= 121.156, p < 0.001, respectively), while triglyceride (TG) was negatively associated with plasma Aβ40, Aβ42, and sRAGE (β= -48.389, p = 0.017; β= -11.142, p = 0.020; β= -147.937, p = 0.003, respectively). Additionally, positive correlations were found between plasma Aβ and sRAGE in the normal TG (Aβ40: β= 0.034, p = 0.005; Aβ42: β= 0.010, p = 0.001) and HDL-c groups (Aβ40: β= 0.023, p = 0.033; Aβ42: β= 0.008, p = 0.002) but not in the high TG and low HDL-c groups. Abnormal levels of TG and HDL-c are associated with decreased Aβ and sRAGE levels. Positive correlations between plasma Aβ and sRAGE were only found in the normal TG and HDL-c groups but not in the high TG and low HDL-c groups. These results indicated that dyslipidemia contributing to plasma Aβ levels might also be involved in peripheral Aβ clearance.

Polysaccharide Krestin Prevents Alzheimer's Disease-type Pathology and Cognitive Deficits by Enhancing Monocyte Amyloid-β Processing.

Deficits in the clearance of amyloid β protein (Aβ) by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer's disease (AD). Impaired uptake of Aβ by dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aβ clearance in AD. In the current study, flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin (PSK) on AD-related pathology in vitro and in vivo. We found that PSK, widely used in therapy for various cancers, has the potential to enhance Aβ uptake and intracellular processing by human monocytes in vitro. After administration of PSK by intraperitoneal injection, APP/PS1 mice performed better in behavioral tests, along with reduced Aβ deposition, neuroinflammation, neuronal loss, and tau hyperphosphorylation. These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aβ clearance by blood monocytes and alleviating AD-like pathology.

Amyloid beta emerges from below the neck to disable the brain.

Accumulation of amyloid beta (Aβ) in the brain in Alzheimer disease drives pathophysiology. A study in this issue of PLOS Biology revealed that Aβ from the liver can promote brain pathology, supporting that peripheral Aβ can contribute to neurodegeneration.

Near-infrared target enhanced peripheral clearance of amyloid-β in Alzheimer's disease model

Clearance of peripheral amyloid-β (Aβ) has been demonstrated particularly promising for overcoming the blood-brain barrier (BBB) hurdle to remove brain-derived Aβ associated with Alzheimer's disease (AD). However, currently used therapeutic agents targeting peripheral Aβ cannot simultaneously achieve plasma Aβ enrichment and enhanced clearance, which may result in poor bioavailability and rather low efficacy. Moreover, most of therapeutic agents usually promote the unfavorable aggregation of Aβ. Herein, we construct a near-infrared (NIR) regulated surface-transformable and target peptide-guided upconversion platform (UCNP/ONA-P/K), serving as a safe and effective way for Aβ clearance. Taking advantage of extended blood circulation, high selectivity toward Aβ, and surface-transformable property, such UCNP/ONA-P/K can address the challenges of peripheral Aβ clearance by a combination of enhancing the enrichment of plasma Aβ, preventing the unfavorable aggregation of Aβ and simultaneously facilitating the hepatic clearance of the captured Aβ. After verified by a series of systematic toxicity evaluation, cell uptake, deep tissue penetration, and hemolytic experiments, in vivo studies demonstrate that UCNP/ONA-P/K can efficiently decrease brain Aβ burden and reverse memory deficits in 3xTg-AD mice. Overall, this NIR multi-functional design provides a new biocompatible and efficient way for Aβ removal, which will promote the application of peripheral clearance of Aβ for AD treatment.