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Nature Immunology Nov 2023Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD...
Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk.
Topics: Animals; Humans; Mice; Alzheimer Disease; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Brain; Homeostasis; Mice, Transgenic; Microglia; Plaque, Amyloid
PubMed: 37857825
DOI: 10.1038/s41590-023-01640-9 -
Neurobiology of Disease May 2020Alzheimer's disease (AD) is a devastating neurodegenerative disorder that is growing in prevalence globally. It is the only major cause of death without any effective... (Review)
Review
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that is growing in prevalence globally. It is the only major cause of death without any effective pharmacological means to treat or slow progression. Inheritance of the ε4 allele of the Apolipoprotein (APO) E gene is the strongest genetic risk factor for late-onset AD. The interaction between APOE and amyloid β (Aβ) plays a key role in AD pathogenesis. The APOE-Aβ interaction regulates Aβ aggregation and clearance and therefore directly influences the development of amyloid plaques, congophilic amyloid angiopathy and subsequent tau related pathology. Relatively few AD therapeutic approaches have directly targeted the APOE-Aβ interaction thus far. Here we review the critical role of APOE in the pathogenesis of AD and some of the most promising therapeutic approaches that focus on the APOE-Aβ interaction.
Topics: Alleles; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoprotein E4; Apolipoproteins E; Brain; Drug Delivery Systems; Humans; Mice; Plaque, Amyloid
PubMed: 32027932
DOI: 10.1016/j.nbd.2020.104784 -
Kidney International Feb 2020Of the glomerular disorders that occur due to apolipoprotein E (apoE) mutations, apoE2 homozygote glomerulopathy and lipoprotein glomerulopathy (LPG) have been... (Review)
Review
Of the glomerular disorders that occur due to apolipoprotein E (apoE) mutations, apoE2 homozygote glomerulopathy and lipoprotein glomerulopathy (LPG) have been characterized. ApoE2 homozygote glomerulopathy has been found in individuals expressing homozygous apoE2/2. This was characterized histologically by glomerulosclerosis with marked infiltration of foam cells derived from macrophages, and occasionally with non-lamellated lipoprotein thrombi. Recently, several cases of apoE Toyonaka (Ser197Cys) combined with homozygous apoE2/2 have been reported, in which non-immune membranous nephropathy-like features were observed in glomeruli. Interestingly, in these cases, apoE accumulation was identified by tandem mass spectrometry. Therefore, it is speculated that these findings may arise from apoE molecules without lipids, which result from hinge damage by apoE Toyonaka and may cross the glomerular basement membrane as small molecules. LPG is primarily associated with heterozygous apoE mutations surrounding the low-density lipoprotein-receptor binding site, and it is histologically characterized by lamellated lipoprotein thrombi that lack foam cells. Recent studies have suggested that LPG can be induced by thermodynamic destabilization, hydrophobic surface exposure, and the aggregation of apoE resulting from the incompatibility of apoE mutated residues within helical regions. Additionally, apoE5 may play a supporting role in the development of LPG and in lipid-induced kidney diseases via hyperlipoproteinemia. Thus, it is interesting that many apoE mutations contribute to characteristic glomerular disorders through various mechanisms. In particular, macrophages may uptake lipoproteins into the cytoplasm and contribute to the development of apoE2 homozygote glomerulopathy as foam cells, and their dysfunction may contribute to the accumulation of lipoproteins in the glomerulus, causing lipoprotein thrombi in LPG.
Topics: Apolipoprotein E2; Apolipoproteins E; Homozygote; Humans; Kidney Diseases; Kidney Glomerulus
PubMed: 31874799
DOI: 10.1016/j.kint.2019.10.031 -
Cell Reports Oct 2023Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant...
Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.
Topics: Humans; Apolipoprotein E4; Astrocytes; Oxidative Phosphorylation; Cells, Cultured; Induced Pluripotent Stem Cells; Apolipoprotein E3; Cholesterol; Alzheimer Disease; Apolipoproteins E
PubMed: 37777962
DOI: 10.1016/j.celrep.2023.113183 -
International Journal of Molecular... Aug 2022A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and... (Review)
Review
A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer's disease. The human gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders.
Topics: Animals; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Atherosclerosis; Cardiovascular Diseases; Humans; Mice; Receptors, LDL
PubMed: 36077289
DOI: 10.3390/ijms23179892 -
Molecular Neurodegeneration Dec 2023Apolipoprotein E (APOE) is the single greatest genetic risk factor for late onset Alzheimer's disease (AD). Yet, the cell-specific effects of APOE on microglia function...
Apolipoprotein E (APOE) is the single greatest genetic risk factor for late onset Alzheimer's disease (AD). Yet, the cell-specific effects of APOE on microglia function have remained unclear. Fortunately, two comprehensive new studies published in the latest issue of Nature Immunology have employed complementary gain-of-function and loss-of-function approaches to provide critical new insight into the impact of microglial APOE on AD pathogenesis.
Topics: Humans; Animals; Mice; Apolipoprotein E4; Microglia; Apolipoprotein E3; Alzheimer Disease; Apolipoproteins E; Mice, Transgenic
PubMed: 38115077
DOI: 10.1186/s13024-023-00693-6 -
Alzheimer's & Dementia : the Journal of... Feb 2024We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological...
INTRODUCTION
We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological interactions between ApoE3Ch and heparan sulfate proteoglycans (HSPGs).
METHODS
We developed and characterized the binding, structure, and preclinical efficacy of novel antibodies targeting human ApoE-HSPG interactions.
RESULTS
We found that one of these antibodies, called 7C11, preferentially bound ApoE4, a major risk factor for sporadic AD, and disrupts heparin-ApoE4 interactions. We also determined the crystal structure of a Fab fragment of 7C11 and used computer modeling to predict how it would bind to ApoE. When we tested 7C11 in mouse models, we found that it reduced recombinant ApoE-induced tau pathology in the retina of MAPT*P301S mice and curbed pTau S396 phosphorylation in brains of systemically treated APOE4 knock-in mice. Targeting ApoE-HSPG interactions using 7C11 antibody may be a promising approach to developing new therapies for AD.
Topics: Mice; Humans; Animals; Apolipoprotein E4; Heparan Sulfate Proteoglycans; Phosphorylation; Apolipoproteins E; Alzheimer Disease; Immunologic Factors; Apolipoprotein E3
PubMed: 37791598
DOI: 10.1002/alz.13436 -
Life Science Alliance Aug 2023Apolipoprotein E4 (ApoE4) is the most important genetic risk factor for Alzheimer's disease (AD). Among the earliest changes in AD is endosomal enlargement in neurons,...
Apolipoprotein E4 (ApoE4) is the most important genetic risk factor for Alzheimer's disease (AD). Among the earliest changes in AD is endosomal enlargement in neurons, which was reported as enhanced in ApoE4 carriers. ApoE is thought to be internalized into endosomes of neurons, whereas β-amyloid (Aβ) accumulates within neuronal endosomes early in AD. However, it remains unknown whether ApoE and Aβ intersect intracellularly. We show that internalized astrocytic ApoE localizes mostly to lysosomes in neuroblastoma cells and astrocytes, whereas in neurons, it preferentially localizes to endosomes-autophagosomes of neurites. In AD transgenic neurons, astrocyte-derived ApoE intersects intracellularly with amyloid precursor protein/Aβ. Moreover, ApoE4 increases the levels of endogenous and internalized Aβ in neurons. Taken together, we demonstrate differential localization of ApoE in neurons, astrocytes, and neuron-like cells, and show that internalized ApoE intersects with amyloid precursor protein/Aβ in neurons, which may be of considerable relevance to AD.
Topics: Humans; Amyloid beta-Protein Precursor; Apolipoprotein E4; Apolipoproteins E; Amyloid beta-Peptides; Alzheimer Disease; Neurons
PubMed: 37290814
DOI: 10.26508/lsa.202201887 -
Neurobiology of Aging Jul 2023C-reactive protein (CRP) impacts apolipoprotein E4 (ApoE4) allele to increase Alzheimer's disease (AD) risk. However, it is unclear how the ApoE protein and its binding...
C-reactive protein (CRP) impacts apolipoprotein E4 (ApoE4) allele to increase Alzheimer's disease (AD) risk. However, it is unclear how the ApoE protein and its binding to LRP1 are involved. We found that ApoE2 carriers had the highest but ApoE4 carriers had the lowest concentrations of blood ApoE in both humans and mice; blood ApoE concentration was negatively associated with AD risk. Elevation of peripheral monomeric CRP (mCRP) reduced the expression of ApoE in ApoE2 mice, while it decreased ApoE-LRP1 binding in the brains of ApoE4 mice that was characterized by Proximity Ligation Assay. Both serum ApoE and brain ApoE-LRP1 binding were positively associated with the expression of pericytes that disappeared after mCRP treatment, and negatively associated with brain tauopathy and neuroinflammation in the presence of mCRP. In ApoE mice, mCRP reduced the brain expression levels of synaptophysin and PSD95 and the positive relationship between ApoE-LRP1 binding and synaptophysin or PSD95 expression disappeared. Our study suggests that blood ApoE protects against AD pathogenesis by binding to LRP1 during peripheral chronic inflammation.
Topics: Humans; Mice; Animals; Alzheimer Disease; Apolipoprotein E2; Apolipoprotein E4; Synaptophysin; Apolipoproteins E; Brain; Inflammation; Apolipoprotein E3; Low Density Lipoprotein Receptor-Related Protein-1
PubMed: 37060729
DOI: 10.1016/j.neurobiolaging.2023.02.013 -
Biochemical and Biophysical Research... Jan 2024Glaucoma is a chronic blinding eye disease caused by the progressive loss of retinal ganglion cells (RGCs). Currently, no clinically approved treatment can directly... (Review)
Review
Glaucoma is a chronic blinding eye disease caused by the progressive loss of retinal ganglion cells (RGCs). Currently, no clinically approved treatment can directly improve the survival rate of RGCs. The Apolipoprotein E (APOE) gene is closely related to the genetic risk of numerous neurodegenerative diseases and has become a hot topic in the field of neurodegenerative disease research in recent years. The optic nerve and retina are extensions of the brain's nervous system. The pathogenesis of retinal degenerative diseases is closely related to the degenerative diseases of the nerves in the brain. APOE consists of three alleles, ε4, ε3, and ε2, in a single locus. They have varying degrees of risk for glaucoma. APOE4 and the APOE gene deletion (APOE) can reduce RGC loss. By contrast, APOE3 and the overall presence of APOE genes (APOE) result in significant loss of RGC bodies and axons, increasing the risk of glaucoma RGCs death. Currently, there is no clear literature indicating that APOE2 is beneficial or harmful to glaucoma. This study summarises the mechanism of different APOE genes in glaucoma and speculates that APOE targeted intervention may be a promising method for protecting against RGCs loss in glaucoma.
Topics: Humans; Apolipoproteins E; Glaucoma; Neurodegenerative Diseases; Retina; Retinal Degeneration
PubMed: 38145596
DOI: 10.1016/j.bbrc.2023.149414