LRP1 Has a Predominant Role in Production over Clearance of Aβ in a Mouse Model of Alzheimer’s Disease (original) (raw)
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Current Pharmaceutical Design, 2008
Low-density lipoprotein receptor related protein-1 (LRP) is a member of the low-density lipoprotein (LDL) receptor family which has been linked to Alzheimer's disease (AD) by biochemical and genetic evidence. Levels of neurotoxic amyloid-peptide (Aβ) in the brain are elevated in AD contributing to the disease process and neuropathology. Faulty A clearance from the brain appears to mediate focal Aβ accumulations in AD. Central and peripheral production of Aβ from Aβprecursor protein (APP), transport of peripheral Aβ into the brain across the blood-brain barrier (BBB) via receptor for advanced glycation end products (RAGE), enzymatic Aβ degradation, Aβ oligomerization and aggregation, neuroinflammatory changes and microglia activation, and Aβ elimination from brain across the BBB by cell surface LRP; all may control brain Aβ levels. Recently, we have shown that a soluble form of LRP (sLRP) binds 70 to 90 % of plasma Aβ, preventing its access to the brain. In AD individuals, the levels of LRP at the BBB are reduced, as are levels of Aβ binding to sLRP in plasma. This, in turn, may increase Aβ brain levels through a decreased efflux of brain Aβ at the BBB and/or reduced sequestration of plasma Aβ associated with re-entry of free Aβ into the brain via RAGE. Thus, therapies which increase LRP expression at the BBB and/or enhance the peripheral Aβ "sink" activity of sLRP, hold potential to control brain Aβ accumulations, neuroinflammation and cerebral blood flow reductions in AD.
LRP/Amyloid β-Peptide Interaction Mediates Differential Brain Efflux of Aβ Isoforms
Neuron, 2004
LRP (low-density lipoprotein receptor-related protein) is linked to Alzheimer's disease (AD). Here, we report amyloid beta-peptide Abeta40 binds to immobilized LRP clusters II and IV with high affinity (Kd = 0.6-1.2 nM) compared to Abeta42 and mutant Abeta, and LRP-mediated Abeta brain capillary binding, endocytosis, and transcytosis across the mouse blood-brain barrier are substantially reduced by the high beta sheet content in Abeta and deletion of the receptor-associated protein gene. Despite low Abeta production in the brain, transgenic mice expressing low LRP-clearance mutant Abeta develop robust Abeta cerebral accumulations much earlier than Tg-2576 Abeta-overproducing mice. While Abeta does not affect LRP internalization and synthesis, it promotes proteasome-dependent LRP degradation in endothelium at concentrations > 1 microM, consistent with reduced brain capillary LRP levels in Abeta-accumulating transgenic mice, AD, and patients with cerebrovascular beta-amyloidosis. Thus, low-affinity LRP/Abeta interaction and/or Abeta-induced LRP loss at the BBB mediate brain accumulation of neurotoxic Abeta.
Pharmacology & therapeutics, 2012
Low-density lipoprotein receptor-related protein-1 (LRP1) is the main cell surface receptor involved in brain and systemic clearance of the Alzheimer's disease (AD) toxin amyloid-beta (Aβ). In plasma, a soluble form of LRP1 (sLRP1) is the major transport protein for peripheral Aβ. LRP1 in brain endothelium and mural cells mediates Aβ efflux from brain by providing a transport mechanism for Aβ across the blood-brain barrier (BBB). sLRP1 maintains a plasma 'sink' activity for Aβ through binding of peripheral Aβ which in turn inhibits re-entry of free plasma Aβ into the brain. LRP1 in the liver mediates systemic clearance of Aβ. In AD, LRP1 expression at the BBB is reduced and Aβ binding to circulating sLRP1 is compromised by oxidation. Cell surface LRP1 and circulating sLRP1 represent druggable targets which can be therapeutically modified to restore the physiological mechanisms of brain Aβ homeostasis. In this review, we discuss how increasing LRP1 expression at the BBB a...
Alzheimer's Research & Therapy, 2012
Introduction: The low-density lipoprotein receptor-related protein (LRP1) and its family members have been implicated in the pathogenesis of Alzheimer's disease. Multiple susceptibility factors converge to metabolic pathways that involve LRP1, including modulation of the processing of amyloid precursor protein (APP) and the clearance of Aβ peptide. Methods: We used the Cre-lox system to lower LRP1 levels in hippocampal neurons of mice that develop Alzheimer-type amyloid by crosses between mice that express Cre recombinase under the transcriptional control of the GFAP promoter, mice that harbor loxp sites in the LRP1 gene, and the APPswe/PS1dE9 transgenic model. We compared amyloid plaque numbers in APPswe/PS1dE9 mice lacking LRP1 expression in hippocampus (n = 13) to mice with normal levels of LRP1 (n = 12). Student t-test was used to test whether there were significant differences in plaque numbers and amyloid levels between the groups. A regression model was used to fit two regression lines for these groups, and to compare the rates of Aβ accumulation. Results: Immunohistochemical analyses demonstrated efficient elimination of LRP1 expression in the CA fields and dentate gyrus of the hippocampus. Within hippocampus, we observed no effect on the severity of amyloid deposition, the rate of Aβ40/42 accumulation, or the architecture of amyloid plaques when LRP1 levels were reduced. Conclusions: Expression of LRP1 by neurons in proximity to senile amyloid plaques does not appear to play a major role in modulating the formation of these proximal deposits or in the appearance of the associated neuritic pathology.
Clearance of amyloid-β by circulating lipoprotein receptors
Nature Medicine, 2007
Low-density lipoprotein receptor-related protein-1 (LRP) on brain capillaries clears amyloid βpeptide (Aβ) from brain. Here, we show that soluble circulating LRP (sLRP) provides key endogenous peripheral 'sink' activity for Aβ in humans. Recombinant LRP cluster IV (LRP-IV) bound Aβ in plasma in mice and in Alzheimer's disease-affected humans with compromised sLRPmediated Aβ binding, and reduced Aβ-related pathology and dysfunction in a mouse model of Alzheimer mice, suggesting LRP-IV can effectively replace native sLRP and clear Aβ.
Experimental Neurology, 2010
Beta-Site APP cleaving enzyme 1 (BACE1) Low-density lipoprotein receptor-related protein 1 (LRP1) Alzheimer's disease (AD) Cleavage of APP by BACE1 is the first proteolytic step in the production of amyloid-beta (Aβ), which accumulates in senile plaques in Alzheimer's disease. Through its interaction with APP, the low-density receptor-related protein 1 (LRP1) enhances APP internalization. Recently, BACE1 has been shown to interact with and cleave the light chain (lc) of LRP1. Since LRP1 is known to compete with APP for cleavage by gamma-secretase, we tested the hypothesis that LRP1 also acts as a competitive substrate for β-secretase. We found that the increase in secreted APP (sAPP) mediated by over-expression of BACE1 in APP-transfected cells could be decreased by simultaneous LRP1 over-expression. Analysis by multi-spot ELISA revealed that this is due to a decrease in sAPPβ, but not sAPPα. Interaction between APP and BACE1, as measured by immunoprecipitation and fluorescence lifetime assays, was impaired by LRP1 over-expression. We also demonstrate that APP over-expression leads to decreased LRP1 association with and cleavage by BACE1. In conclusion, our data suggest thatin addition to its role in APP trafficking-LRP1 affects APP processing by competing for cleavage by BACE1.
Alzheimer's & Dementia, 2012
Background: The Aβ peptide that accumulates in Alzheimer's disease (AD) is derived from amyloid precursor protein (APP) following proteolysis by βand γ-secretases. Substantial evidence indicates that alterations in APP trafficking within the secretory and endocytic pathways directly impact the interaction of APP with these secretases and subsequent Aβ production. Various members of the low-density lipoprotein receptor (LDLR) family have been reported to play a role in APP trafficking and processing and are important risk factors in AD. We recently characterized a distinct member of the LDLR family called LDLR-related protein 10 (LRP10) that shuttles between the trans-Golgi Network (TGN), plasma membrane (PM), and endosomes. Here we investigated whether LRP10 participates in APP intracellular trafficking and Aβ production.
Neuron, 2009
Apolipoprotein E (APOE) is the strongest genetic risk factor for Alzheimer's disease (AD). Previous studies suggest that the effect of apoE on amyloid-β (Aβ) accumulation plays a major role in AD pathogenesis. Therefore, understanding proteins that control apoE metabolism may provide new targets for regulating Aβ levels. LDLR, a member of the LDL receptor family, binds to apoE, yet its potential role in AD pathogenesis remains unclear. We hypothesized that LDLR overexpression in the brain would decrease apoE levels, enhance Aβ clearance and decrease Aβ deposition. To test our hypothesis, we created several transgenic mice that overexpress LDLR in the brain and found that apoE levels in these mice decreased by 50-90%. Furthermore, LDLR overexpression dramatically reduced Aβ aggregation and enhanced Aβ clearance from the brain extracellular space. Plaque-associated neuroinflammatory responses were attenuated in LDLR transgenic mice. These findings suggest that increasing LDLR levels may represent a novel AD treatment strategy.
Molecular Neurodegeneration
Background: Clearance at the blood-brain barrier (BBB) plays an important role in removal of Alzheimer's amyloid-β (Aβ) toxin from brain both in humans and animal models. Apolipoprotein E (apoE), the major genetic risk factor for AD, disrupts Aβ clearance at the BBB. The cellular and molecular mechanisms, however, still remain unclear, particularly whether the BBBassociated brain capillary pericytes can contribute to removal of aggregated Aβ from brain capillaries, and whether removal of Aβ aggregates by pericytes requires apoE, and if so, is Aβ clearance on pericytes apoE isoform-specific. Methods: We performed immunostaining for Aβ and pericyte biomarkers on brain capillaries (< 6 μm in diameter) on tissue sections derived from AD patients and age-matched controls, and APP Swe/0 mice and littermate controls. Human Cy3-Aβ42 uptake by pericytes was studied on freshly isolated brain slices from control mice, pericyte LRP1-deficient mice (Lrp lox/lox ; Cspg4-Cre) and littermate controls. Clearance of aggregated Aβ42 by mouse pericytes was studied on multi-spot glass slides under different experimental conditions including pharmacologic and/or genetic inhibition of the low density lipoprotein receptor related protein 1 (LRP1), an apoE receptor, and/or silencing mouse endogenous Apoe in the presence and absence of human astrocyte-derived lipidated apoE3 or apoE4. Student's t-test and one-way ANOVA followed by Bonferroni's posthoc test were used for statistical analysis. Results: First, we found that 35% and 60% of brain capillary pericytes accumulate Aβ in AD patients and 8.5-month-old APP Sw/0 mice, respectively, compared to negligible uptake in controls. Cy3-Aβ42 species were abundantly taken up by pericytes on cultured mouse brain slices via LRP1, as shown by both pharmacologic and genetic inhibition of LRP1 in pericytes. Mouse pericytes vigorously cleared aggregated Cy3-Aβ42 from multi-spot glass slides via LRP1, which was inhibited by pharmacologic and/or genetic knockdown of mouse endogenous apoE. Human astrocyte-derived lipidated apoE3, but not apoE4, normalized Aβ42 clearance by mouse pericytes with silenced mouse apoE. Conclusions: Our data suggest that BBB-associated pericytes clear Aβ aggregates via an LRP1/apoE isoform-specific mechanism. These data support the role of LRP1/apoE interactions on pericytes as a potential therapeutic target for controlling Aβ clearance in AD.