Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele ...conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.
Abstract Apolipoprotein E (apoE) is a lipid carrier in both periphery and the central nervous system (CNS). Lipid-loaded apoE lipoprotein particles bind to several cell surface receptors to support ...membrane homeostasis and injury repair in the brain. Considering prevalence and relative risk magnitude, the ε4 allele of the APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE4 contributes to AD pathogenesis by modulating multiple pathways including but not limited to the metabolism, aggregation, and toxicity of amyloid-β (Aβ) peptide, tauopathy, synaptic plasticity, lipid transport, glucose metabolism, mitochondrial function, vascular integrity, and neuroinflammation. Emerging knowledge on apoE-related pathways in the pathophysiology of AD presents new opportunities for AD therapy. In this Review, we describe the biochemical and biological features of apoE and apoE receptors in the CNS. We also discuss the evidence and mechanisms addressing differential effects of apoE isoforms and the role of apoE receptors in AD pathogenesis, with a particular emphasis on the clinical and preclinical studies related to Aβ pathology. Finally, we summarize the current strategies of AD therapy targeting apoE, and postulate that effective strategies require an apoE isoform-specific approach.
Accumulation and aggregation of amyloid-β (Aβ) in the brain is an initiating step in the pathogenesis of Alzheimer’s disease (AD). The ε4 allele of apolipoprotein E (apoE) gene is the strongest ...genetic risk factor for late-onset AD. Although there is strong evidence showing that apoE4 enhances amyloid pathology, it is not clear what the critical stage(s) is during amyloid development in which apoE4 has the strongest impact. Using apoE inducible mouse models, we show that increased expression of astrocytic apoE4, but not apoE3, during the seeding stage of amyloid development enhanced amyloid deposition and neuritic dystrophy in amyloid model mice. ApoE4, but not apoE3, significantly increased brain Aβ half-life measured by in vivo microdialysis. Furthermore, apoE4 expression increased whereas apoE3 reduced amyloid-related gliosis in the mouse brains. Together, our results demonstrate that apoE4 has the greatest impact on amyloid during the seeding stage, likely by perturbing Aβ clearance and enhancing Aβ aggregation.
•ApoE4 drives amyloid pathology during the seeding stage•ApoE4 has minimal effect on amyloidosis during the plaque rapid growth period•ApoE isoforms differentially affect amyloid plaque-associated neuroinflammation•Strategies targeting apoE4 to reduce Aβ pathology should focus on early prevention
Liu et al. have developed cell-type-specific and inducible apoE mouse models and demonstrate that astrocytic apoE4 is a potent factor in promoting amyloidosis during the seeding stage, but not the rapid growth period, of amyloid development. ApoE4 impairs Aβ clearance and accelerates Aβ aggregation, leading to enhanced amyloid pathology and neuritic dystrophy.
A man with ST segment depression Chen, Chia-Chen; Shao, Jiayi; Liu, Yuchen ...
BMJ (Online),
09/2023, Letnik:
382
Journal Article
Recenzirano
ECG at myocardial infarction nine years before this presentation Initial physical examination showed his body temperature to be 36.4°C, blood pressure 126/106 mm Hg, pulse rate 95 beats/min, and ...respiratory rate 16 breaths/min. The ECG pattern is observed in approximately 2% of all patients presenting with an anterior wall myocardial infarction.4 According to three diagnostic studies, the de Winter pattern showed positive predictive values of 95.2% (95% confidence interval 76.2 to 99.9%), 100% (69.2 to 100.0%), and 100% (51.7 to 100%) for acute occlusion of the LAD.456 These results indicate that the pattern has a high positive predictive value for acute occlusion. 3. The de Winter ECG pattern is recognised as a ST elevation myocardial infarction (STEMI) equivalent, and dual antiplatelet therapy, heparin, and immediate reperfusion with primary percutaneous coronary intervention are recommend in most patients.78 Not all STEMI equivalents present with an elevated troponin I because troponin may not be released into the bloodstream until reperfusion occurs, owing to abrupt coronary occlusion. ...if troponin levels are within the normal range but there is a high clinical suspicion of myocardial infarction, promptly initiate therapeutic measures and refer for urgent coronary angiography.9 Learning point The de Winter ECG pattern is a STEMI equivalent, highly suggestive of LAD occlusion Key ECG features include up-sloping ST segment depression, tall symmetrical T waves in precordial leads, and ST elevation in aVR Patients with the de Winter pattern should undergo immediate reperfusion therapy.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer's disease (AD). A proteolytic product, soluble TREM2 (sTREM2), ...is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number of genetic risk ...factors identified, the apolipoprotein E (
APOE
) gene remains the strongest and most prevalent, impacting more than half of all AD cases. While the ε4 allele of the
APOE
gene significantly increases AD risk, the ε2 allele is protective relative to the common ε3 allele. These gene alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function of apoE is to mediate lipid transport in the brain and periphery; however, additional functions of apoE in diverse biological functions have been recognized. Pathogenically, apoE seeds amyloid-β (Aβ) plaques in the brain with apoE4 driving earlier and more abundant amyloids. ApoE isoforms also have differential effects on multiple Aβ-related or Aβ-independent pathways. The complexity of apoE biology and pathobiology presents challenges to designing effective apoE-targeted therapeutic strategies. This review examines the key pathobiological pathways of apoE and related targeting strategies with a specific focus on the latest technological advances and tools.
Diabetes and impaired brain insulin signaling are linked to the pathogenesis of Alzheimer’s disease (AD). The association between diabetes and AD-associated amyloid pathology is stronger among ...carriers of the apolipoprotein E (APOE) ε4 gene allele, the strongest genetic risk factor for late-onset AD. Here we report that apoE4 impairs neuronal insulin signaling in human apoE-targeted replacement (TR) mice in an age-dependent manner. High-fat diet (HFD) accelerates these effects in apoE4-TR mice at middle age. In primary neurons, apoE4 interacts with insulin receptor and impairs its trafficking by trapping it in the endosomes, leading to impaired insulin signaling and insulin-stimulated mitochondrial respiration and glycolysis. In aging brains, the increased apoE4 aggregation and compromised endosomal function further exacerbate the inhibitory effects of apoE4 on insulin signaling and related functions. Together, our study provides novel mechanistic insights into the pathogenic mechanisms of apoE4 and insulin resistance in AD.
•ApoE4 impairs cerebral insulin signaling in an age-dependent manner•Peripheral insulin resistance and apoE4 synergistically impair insulin signaling•ApoE4 reduces insulin-IR interaction and impairs IR trafficking•ApoE4 aggregation and endosomal dysfunction impair insulin signaling with aging
Zhao et al. demonstrates that aging and peripheral insulin resistance induces impairment of cerebral insulin signaling in human apoE4-targeted replacement mice. ApoE4 interferes with insulin receptor signaling by blocking its interaction with insulin and trapping the receptor in the endosomes.
APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer's disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem ...cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the ...cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type and
-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.
Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease ...(AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Review, we describe current knowledge on Apo-E in the CNS, with a particular emphasis on the clinical and pathological features associated with carriers of different Apo-E isoforms. We also discuss Aβ-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk, and consider how to design effective strategies for AD therapy by targeting Apo-E.
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