The vast majority of Alzheimer's disease (AD) cases are late-onset and their development is probably influenced by both genetic and environmental risk factors. A strong genetic risk factor for ...late-onset AD is the presence of the epsilon4 allele of the apolipoprotein E (APOE) gene, which encodes a protein with crucial roles in cholesterol metabolism. There is mounting evidence that APOE4 contributes to AD pathogenesis by modulating the metabolism and aggregation of amyloid-beta peptide and by directly regulating brain lipid metabolism and synaptic functions through APOE receptors. Emerging knowledge of the contribution of APOE to the pathophysiology of AD presents new opportunities for AD therapy.
Because Aβ deposition triggers or accelerates additional pathogenic events including microglia-mediated immune response and tau tangle spread, effective strategy targeting Aβ will likely be primary ...prevention prior to plaque development. ...APOE genotype also has differential effects on age-related cognitive decline and Lewy body dementia parallel to their risk profile for AD. Preclinical studies using animal models and cellular models are needed to address specific effects of this variant on neuropathological features (i.e., amyloid plaques and tau tangles), immune response, lipid metabolism, vascular integrity and function, and other AD-related pathways. ...the R251G mutation could potentially change the apoE4 structure such that it either reduces its harmful effects or enhances its physiological functions 1.
Among the LDL receptor (LDLR) family members, the roles of LDLR-related protein (LRP)1 in the pathogenesis of Alzheimer's disease (AD), especially late-onset AD, have been the most studied by ...genetic, neuropathological, and biomarker analyses (clinical studies) or cellular and animal model systems (preclinical studies) over the last 25 years. Although there are some conflicting reports, accumulating evidence from preclinical studies indicates that LRP1 not only regulates the metabolism of amyloid-β peptides (Aβs) in the brain and periphery, but also maintains brain homeostasis, impairment of which likely contributes to AD development in Aβ-independent manners. Several preclinical studies have also demonstrated an involvement of LRP1 in regulating the pathogenic role of apoE, whose gene is the strongest genetic risk factor for AD. Nonetheless, evidence from clinical studies is not sufficient to conclude how LRP1 contributes to AD development. Thus, despite very promising results from preclinical studies, the role of LRP1 in AD pathogenesis remains to be further clarified. In this review, we discuss the potential mechanisms underlying how LRP1 affects AD pathogenesis through Aβ-dependent and -independent pathways by reviewing both clinical and preclinical studies. We also discuss potential therapeutic strategies for AD by targeting LRP1.
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.
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.
Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer's disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common ...coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition, APOE*ε2 has been identified as a longevity gene, suggesting a systemic effect of APOE*ε2 on the aging process. However, APOE*ε2 is not entirely benign; APOE*ε2 carriers exhibit increased risk of certain cerebrovascular diseases and neurological disorders. Here, we review evidence from both human and animal studies demonstrating the protective effect of APOE*ε2 against AD and propose a working model depicting potential underlying mechanisms. Finally, we discuss potential therapeutic strategies designed to leverage the protective effect of APOE2 to treat AD.
Alzheimer's disease (AD) is characterized pathologically by the deposition of β-amyloid peptides (Aβ) and the accumulation of neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau. ...Regardless of the pathological hallmarks, synaptic dysfunction is widely accepted as a causal event in AD. Of the two major types of synapses in the central nervous system (CNS): glutamatergic and GABAergic, which provide excitatory and inhibitory outputs respectively, abundant data implicate an impaired glutamatergic system during disease progression. However, emerging evidence supports the notion that disrupted default neuronal network underlies impaired memory, and that alterations of GABAergic circuits, either plays a primary role or as a compensatory response to excitotoxicity, may also contribute to AD by disrupting the overall network function. The goal of this review is to provide an overview of the involvement of Aβ, tau and apolipoprotein E4 (apoE4), the major genetic risk factor in late-onset AD (LOAD), in GABAergic neurotransmission and the potential of modulating the GABAergic function as AD therapy.
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 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.
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