更新于：2024-11-01

APP x LRP1

更新于：2024-11-01

基本信息

关联

项与 APP x LRP1 相关的药物

MT007-LRPIV

靶点

APP x LRP1

作用机制

APP抑制剂 [+1]

在研机构-

原研机构

Socratech LLC

在研适应症-

非在研适应症

阿尔茨海默症

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 APP x LRP1 相关的临床结果

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100 项与 APP x LRP1 相关的转化医学

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0 项与 APP x LRP1 相关的专利（医药）

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142

项与 APP x LRP1 相关的文献（医药）

2024-12-31·Gut Microbes

Modulation of Alzheimer’s disease brain pathology in mice by gut bacterial depletion: the role of IL-17a

Article

作者: Hao, Wenlin ; Tomic, Inge ; Liu, Yang ; Luo, Qinghua ; Fassbender, Klaus ; Quan, Wenqiang ; Menger, Michael D ; Hartmann, Tobias

Gut bacteria regulate brain pathology of Alzheimer's disease (AD) patients and animal models; however, the underlying mechanism remains unclear. In this study, 3-month-old APP-transgenic female mice with and without knock-out of Il-17a gene were treated with antibiotics-supplemented or normal drinking water for 2 months. The antibiotic treatment eradicated almost all intestinal bacteria, which led to a reduction in Il-17a-expressing CD4-positive T lymphocytes in the spleen and gut, and to a decrease in bacterial DNA in brain tissue. Depletion of gut bacteria inhibited inflammatory activation in both brain tissue and microglia, lowered cerebral Aβ levels, and promoted transcription of Arc gene in the brain of APP-transgenic mice, all of which effects were abolished by deficiency of Il-17a. As possible mechanisms regulating Aβ pathology, depletion of gut bacteria inhibited β-secretase activity and increased the expression of Abcb1 and Lrp1 in the brain or at the blood-brain barrier, which were also reversed by the absence of Il-17a. Interestingly, a crossbreeding experiment between APP-transgenic mice and Il-17a knockout mice further showed that deficiency of Il-17a had already increased Abcb1 and Lrp1 expression at the blood-brain barrier. Thus, depletion of gut bacteria attenuates inflammatory activation and amyloid pathology in APP-transgenic mice via Il-17a-involved signaling pathways. Our study contributes to a better understanding of the gut-brain axis in AD pathophysiology and highlights the therapeutic potential of Il-17a inhibition or specific depletion of gut bacteria that stimulate the development of Il-17a-expressing T cells.

2024-09-01·International Journal of Biological Macromolecules

Polysaccharides extracted from common buckwheat (Fagopyrum esculentum) attenuate cognitive impairment via suppressing RAGE/p38/NF-κB signaling and dysbiosis in AlCl3-treated rats

Article

作者: Chen, Ying-Ying ; Chang, Hsin-Yu ; Yen, Gow-Chin ; Chen, Sheng-Yi ; Chiang, I-Chen ; Liu, Yu-Chen

Patients may find it challenging to accept several FDA-approved drugs for Alzheimer's disease (AD) treatment due to their unaffordable prices and side effects. Despite the known antioxidant, anti-inflammatory, and microbiota-regulating effects of common buckwheat (Fagopyrum esculentum) polysaccharides (FEP), their specific role in preventing AD has not been determined. Here, this study investigated the preventive effects of FEP on AD development in AlCl₃-treated rats. The physical properties of FEP were evaluated using X-ray diffraction, FTIR, TGA, DSC, monosaccharide composition, molecular weight, and scanning electron microscopy. The results demonstrated that FEP administration improved memory and learning ability in AlCl₃-treated rats. Additionally, AD pathological biomarkers (APP, BACE1, Aβ₁_-₄₂, and p-Tau^Ser404), inflammatory-associated proteins (IL-1β, IL-6, TNF-α, and Iba1), and MDA and the RAGE/p38/NF-κB pathway were elevated in AlCl₃-treated rats. Moreover, these effects were reversed by the upregulation of LRP1, anti-inflammatory cytokines (IL-4 and IL-10), antioxidant enzymes (SOD and catalase), and autophagy proteins (Atg5, Beclin-1, and LC3B). Furthermore, FEP treatment increased the levels of short-chain fatty acids (SCFAs) and the abundance of SCFAs-producing microbes ([Eubacterium]_xylanophilum_group, Lachnospiraceae_NK4A136_group, Lactobacillus). Overall, FEP mitigated oxidative stress, RAGE/p38/NF-κB-mediated neuroinflammation, and AD-associated proteins by upregulating autophagy and SCFA levels, which led to the amelioration of cognitive impairment through microbiota-gut-brain communication in AlCl₃-treated rats.

2024-09-01·Neurobiology of Disease

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

Article

作者: Than, Tin A ; Panchal, Urvashi R ; Han, Derick ; Kaur, Kamaljit ; Roules, G Chuli ; Imiruaye, Oghenetega E ; Kaplowitz, Neil ; Roosan, Moom R ; Win, Sanda ; Sumbria, Rachita K ; Chandrashekar, Devaraj V ; Zhang, Hai ; Garcia, Jerome ; Oyegbesan, Adenike ; Jagadeesan, Nataraj

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.