Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis

Chen, Yun; Strickland, Michael R.; Soranno, Andrea; Holtzman, David M.

doi:10.1016/j.neuron.2020.10.008

Cited by 151 publications

(117 citation statements)

References 155 publications

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“…The cause of the sporadic forms of AD is unknown; the majority of them develop after 65 years of age [39]. The ε-4 allele of the apolipoprotein E (APOE) is a risk factor in the pathogenesis of late-onset of AD, playing an important role in amyloid β (Aβ) brain metabolism (APOE ε-4 exacerbates deposition of Aβ in the brain and tau-mediated neurodegeneration) [40][41][42]. Among various risk factors associated with AD, T2D, traumatic brain injury, cerebrovascular disease, hypertension, dyslipidemia, obesity and metabolic syndrome have been demonstrated [43,44].…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

“…None of the experimental AD animal models fully reflects complete disorders and cognitive impairments characteristic for human AD. Although FAD accounts for about 5% of all disease cases only, the majority of potential therapies has been investigated in transgenic mouse models of AD [42].…”

Section: Experimental Models Of Admentioning

confidence: 99%

“…Transgenic technologies allowed mouse and rat models to be created, based on the mutations of APP, presenilin (PS), APOE and tau protein genes [37,42,96]. Mouse models are the most commonly used in the experimental studies on AD, due to their low prices, relatively short life span and similar AD symptoms to the human disease [96].…”

Section: Experimental Models Of Admentioning

confidence: 99%

“…In the human tau protein (h-tau) transgenic model, the mice tau gene is replaced by the human gene correlating with NFTs development and neurodegeneration [37,42,100,102,103]. The most commonly used tau transgenic model is THY-Tau22 model in which progressive development of the hippocampal tau pathology is observed.…”

Section: Experimental Models Of Admentioning

confidence: 99%

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Potential of Caffeine in Alzheimer’s Disease—A Review of Experimental Studies

et al. 2021

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Alzheimer’s disease (AD) is the most common type of dementia leading to progressive memory loss and cognitive impairment. Considering that pharmacological treatment options for AD are few and not satisfactory, increasing attention is being paid to dietary components that may affect the development of the disease. Such a dietary component may be caffeine contained in coffee, tea or energy drinks. Although epidemiological data suggest that caffeine intake may counteract the development of cognitive impairment, results of those studies are not conclusive. The aim of the present study is to review the existing experimental studies on the efficacy of caffeine against AD and AD-related cognitive impairment, focusing on the proposed protective mechanisms of action. In conclusion, the reports of studies on experimental AD models generally supported the notion that caffeine may exert some beneficial effects in AD. However, further studies are necessary to elucidate the role of caffeine in the effects of its sources on cognition and possibly AD risk.

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Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

Section: Experimental Models Of Admentioning

confidence: 99%

Section: Experimental Models Of Admentioning

confidence: 99%

Section: Experimental Models Of Admentioning

confidence: 99%

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Potential of Caffeine in Alzheimer’s Disease—A Review of Experimental Studies

et al. 2021

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“…The dynamic trafficking and efficient cholesterol transport we observed with ApoE4 agrees with studies in astrocytes (31, 66). In the brain, astrocytes deliver cholesterol to neurons in the form of ApoE lipoproteins (67), and high neuronal cholesterol is conducive for the formation of pathogenic beta-amyloid from amyloid precursor protein, suggesting that increased astrocyte-to-neuron cholesterol transport by ApoE4 is injurious to the brain (66). In contrast, in the retina, the RPE is the main biosynthetic source of ApoE, the primary hub for cholesterol trafficking into and out of the retina, and the initiator of drusen biogenesis (6, 8, 35).…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration

Cunza

Tan

Thamban

et al. 2020

Preprint

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The retinal pigment epithelium (RPE) is the site of initial damage leading to photoreceptor degeneration and vision loss in age-related macular degeneration (AMD). Genetic and histopathological studies implicate cholesterol dysregulation in AMD; yet mechanisms linking cholesterol to RPE injury and drusen formation remain poorly understood. Especially enigmatic are allelic variants of the cholesterol transporter APOE, major risk modifiers in Alzheimer’s disease that show reversed risk associations with AMD. Here, we investigated how ApoE isoforms modulate RPE health using live-cell imaging of primary RPE cultures and high-resolution imaging of human donor tissue. We show that the AMD-protective ApoE4 efficiently transports cholesterol and safeguards RPE homeostasis despite cellular stress. In contrast, ApoE2-expressing RPE accumulate cholesterol, which promotes autophagic deficits and complement-mediated mitochondrial fragmentation. Redox-related order-disorder phase transitions in ApoE2 drive the formation of intracellular biomolecular condensates as potential drusen precursors. Drugs that restore mitochondrial function limit condensate formation in ApoE2-RPE. Autophagic and mitochondrial defects correlate with intracellular ApoE aggregates in AMD donor RPE. Our study elucidates how AMD risk variants act as tipping points to divert the RPE from normal aging towards AMD by disrupting critical metabolic functions, and identifies mitochondrial stress-mediated aberrant phase transitions as a novel mechanism of drusen biogenesis.

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APOE and immunity: Research highlights

Kloske

Barnum²,

Batista

et al. 2023

Alzheimer's & Dementia

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INTRODUCTION:At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODS:The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTS:During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]).DISCUSSION: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.

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Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis

Cited by 151 publications

References 155 publications

Potential of Caffeine in Alzheimer’s Disease—A Review of Experimental Studies

Potential of Caffeine in Alzheimer’s Disease—A Review of Experimental Studies

Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration

APOE and immunity: Research highlights

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