Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (original) (raw)
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PLoS ONE, 2011
Background: Apolipoprotein E (ApoE), a cholesterol carrier associated with atherosclerosis, is a major risk factor for Alzheimer's disease (AD). The low-density lipoprotein receptor (LDLR) regulates ApoE levels in the periphery and in the central nervous system. LDLR has been identified on astrocytes and a number of studies show that it modulates amyloid deposition in AD transgenic mice. However these findings are controversial on whether LDLR deletion is beneficial or detrimental on the AD-like phenotype of the transgenic mice.
Proceedings of the National Academy of Sciences, 2012
The apolipoprotein E (APOE)-ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease, likely increasing risk by altering amyloid-β (Aβ) accumulation. We recently demonstrated that the low-density lipoprotein receptor (LDLR) is a major apoE receptor in the brain that strongly regulates amyloid plaque deposition. In the current study, we sought to understand the mechanism by which LDLR regulates Aβ accumulation by altering Aβ clearance from brain interstitial fluid. We hypothesized that increasing LDLR levels enhances blood-brain barrier-mediated Aβ clearance, thus leading to reduced Aβ accumulation. Using the brain Aβ efflux index method, we found that blood-brain barriermediated clearance of exogenously administered Aβ is enhanced with LDLR overexpression. We next developed a method to directly assess the elimination of centrally derived, endogenous Aβ into the plasma of mice using an anti-Aβ antibody that prevents degradation of plasma Aβ, allowing its rate of appearance from the brain to be measured. Using this plasma Aβ accumulation technique, we found that LDLR overexpression enhances brain-toblood Aβ transport. Together, our results suggest a unique mechanism by which LDLR regulates brain-to-blood Aβ clearance, which may serve as a useful therapeutic avenue in targeting Aβ clearance from the brain. dementia | low-density lipoprotein-related protein 1 | peripheral | in vivo microdialysis | sequestration
Proceedings of the National Academy of Sciences, 2005
Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the ε4 allele increasing and the ε2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-β peptide (Aβ) and amyloid burden, both in humans and in transgenic mice. Here we show that direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal Aβ and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal Aβ 1–42 levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal Aβ burden. Our data demonstrate rapid apoE isoform-dependent effects on brain Aβ burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain Aβ burden and the subsequent development of neuritic plaques.
The Role of Apolipoprotein E in Alzheimer's Disease
Neuron, 2009
The ε4 allele of apolipoprotein E (APOE) is the major genetic risk factor for Alzheimer's disease (AD). Although there have been numerous studies attempting to elucidate the underlying mechanism for this increased risk, the manner in which apoE4 influences AD onset and progression has yet to be proven. However, prevailing evidence suggests that the differential effects of apoE isoforms on Aβ aggregation and clearance play the major role in AD pathogenesis. Other potential mechanisms, such as the differential modulation of neurotoxicity and tau phosphorylation by apoE isoforms as well as its role in synaptic plasticity and neuroinflammation, have not been ruled out. Inconsistent results among studies have made it difficult to define whether the APOE ε4 allele represents a gain of toxic function, a loss of neuroprotective function, or both. Therapeutic strategies based on apoE propose to reduce the toxic effects of apoE4 or to restore the physiological, protective functions of apoE. In addition, modulation of apoE protein levels and lipidation state by low-density lipoprotein (LDL) receptor family members and ATPbinding cassette transporter A1 (ABCA1) may be useful to exploit as future therapeutic targets.
Journal of Alzheimer's disease : JAD, 2017
Neuroinflammation plays a critical role in neuronal dysfunction and death of Alzheimer's disease (AD). ApoE4 is a major risk factor of AD, while ApoE2 is neuroprotective. Little is known about the roles of ApoE isoforms in the neuroinflammation seen in AD. Their roles and mechanisms in Aβ-induced/neuroinflammation were investigated in this study using in vivo and in vitro models. Rat astrocytes were treated with lipid-poor recombinant hApoE or/and Aβ42. Mouse astrocyte lines-expressing lipidated hApoE were treated with Aβ42 or/and vitamin D receptor (VDR) agonist, 1α,25-dihydroxyvitamin D3. Cells and media were harvested for cytokine ELISA, RNA isolated for qRT-PCR, and nuclear protein for transcription factor (TF) arrays and EMSA. hApoE-transgenic and AD mice were mated to generate hApoE2/AD and hApoE4/AD mice. Mice were sacrificed at 6 months of age. Brain tissues were collected for cytokine ELISA array, Aβ ELISA, immunoblotting, and immunohistochemistry. hApoE4/AD mice had si...
Molecular pathogenesis of apolipoprotein E-mediated amyloidosis in late-onset Alzheimer's disease
Cellular and Molecular Life Sciences (CMLS), 1999
Apolipoprotein E (apoE) m4 allele is a genetic Ai deposition. One is the intracellular pathway in which apoE is internalized by neurons and induces lysosomal risk factor for late-onset familial and sporadic accumulation of Ai and amyloidogenic APP (amyloid Alzheimer's disease (AD). In the central nervous system, precursor protein) fragments, leading to neuronal death. apoE is secreted mainly by astrocytes as a constituent of The other is the extracellular pathway in which apoE-high-density lipoproteins. A recent study using apoE containing lipoproteins are trapped by Ai1-42 deposits knockout mice provided strong evidence that apoE promotes cerebral deposition of amyloid i protein (Ai). mobilizing soluble Ai peptides and consequently en-However, no clear explanation of the pathogenesis of large amyloid plaques. These two mechanisms may op-apoE-induced AD has been provided. Here we discuss erate at different stages of AD pathogenesis and suggest two possible mechanisms by which apoE might enhance a chaperone-like function for the apoE molecule Key words. Apolipoprotein E (apoE); Alzheimer's disease (AD); amyloid i protein (Ai); apoE receptor; high-density lipoprotein (HDL).
Apolipoprotein E metabolism and functions in brain and its role in Alzheimerʼs disease
Current Opinion in Lipidology, 2016
Purpose of review APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid b plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid b and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease. Recent findings ApoE isoforms have differential effects on amyloid b metabolism. Recent studies demonstrated that ApoE-interacting proteins, such as ATP-binding cassette A1 (ABCA1) and LDL receptor, may be promising therapeutic targets for Alzheimer's disease treatment. Activation of liver X receptor and retinoid X receptor pathway induces ABCA1 and other genes, leading to amyloid b clearance. Inhibition of the negative regulators of ABCA1, such as microRNA-33, also induces ABCA1 and decreases the levels of ApoE and amyloid b. In addition, genetic inactivation of an E3 ubiquitin ligase, myosin regulatory light chain interacting protein, increases LDL receptor levels and inhibits amyloid accumulation. Although amyloid b-dependent pathways have been extensively investigated, there have been several recent studies linking ApoE with vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcriptional regulation. For example, ApoE was identified as a ligand for a microglial receptor, TREM2, and studies suggested that ApoE may affect the TREM2-mediated microglial phagocytosis. Summary Emerging data suggest that ApoE affects several amyloid b-independent pathways. These underexplored pathways may provide new insights into Alzheimer's disease pathogenesis. However, it will be important to determine to what extent each mechanism contributes to the pathogenesis of Alzheimer's disease.
Journal of Clinical Investigation, 1999
Human apo E4 expression by astrocytes suppresses Aβ deposition, as assessed by anti-Aβ immunostaining in APP V717F+/mice at 39 weeks of age. APP V717F+/-, mouse apo E +/+ animals had numerous hippocampal and some cortical Aβ-IR deposits by 39 weeks of age (a and b). APP V717F+/-, apo E -/animals had less Aβ-IR deposits than those expressing mouse apo E; however, there was still a significant amount of deposition in all animals assessed. In addition, the hippocampal Aβ that was present in apo E -/mice was in a different distribution, with more Aβ immunoreactivity in the hilus of the dentate gyrus and none in the cortex (c and d). In APP V717F+/-, apo E4 +/line 22 animals, hippocampal Aβ immunoreactivity was completely absent in most animals (e and f). Scale bar: 60 µm for b, d, and f; 150 µm for a, c, and e. Aβ, amyloid β; APP, amyloid precursor protein; IR, immunoreactive.
Functional interaction between APOE4 and LDL receptor isoforms in Alzheimer's disease
Journal of Medical Genetics, 2005
Background: Multiple genes have been provisionally associated with Alzheimer's disease, including the coding polymorphisms in exons 8 and 13 in the low density lipoprotein receptor gene (LDLR), situated on chromosome 19p13.2. Methods: The sample groups consisted of 180 AD patients and 141 control spouses. We carried out genotyping of LDLR8 and LDLR13. Results: The LDLR8 GG genotype was common, found in 84% of the unaffected control subjects and 91% of the AD patients in our study. There was a ninefold elevation in risk associated with GG:CC versus A-and T-among APOE4+ subjects when compared with APOE42 subjects (odds ratio 9.3; 95% confidence interval 1.8 to 48.2). With the additional information on LDLR polymorphism, we defined an overall 12 fold elevation in risk for APOE4 in combination with LDLR GG:CC (11.9; 2.8 to 50.0; Fisher's exact test, p = 0.0002; standard power 0.999), compared with other subjects lacking all three of these polymorphisms. Conclusion: These results imply a functional interaction between ApoE and LDL receptor proteins that determines risk for Alzheimer's disease.