Roles of ApoE4 on the Pathogenesis in Alzheimer’s Disease and the Potential Therapeutic Approaches

Sun, Ying; Wang, Zhun; Huang, Han-Chang

doi:10.1007/s10571-023-01365-1

Cited by 23 publications

(8 citation statements)

References 174 publications

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“…To fully capture the impact of space environment on potential cognition deterioration, we also cultured diseased PFC organoids (DPFC), using APOE4/E4 mutation (two alleles of APO4) which is the highest genetic risk factor and most prevalent in AD patients (APOE4 carriers account for 65-80% of all AD cases), and has been shown to induce detrimental effects via amyloid Aβ plaque, neurotoxic fragments, stimulating Tau phosphorylation, and impaired mitochondrial function. [50][51][52][53][54][55][56] In parallel, we also used TDP-43 overexpression (TDP-43 knock-in) in neuronal cells to create diseased MN organoids (or DMN), to induce frontotemporal dementia (FTD) and ALS-mimicking pathology in 3D MN organoids. TDP-43 has been shown to be a key risk and pathological factor for both FTD and ALS, as well as other neurodegenerative diseases.…”

Section: Resultsmentioning

confidence: 99%

Inflammasome-Inhibiting Nanoligomers are Neuroprotective Against Space-Induced Pathology in Healthy and Diseased 3D Human Motor and Pre-Frontal Cortex Brain Organoids

Sharma,

Gilberto,

Rask

et al. 2024

Preprint

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Microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to space astronauts and tourists, and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here we show, a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station (ISS). First, comparing 3D healthy and diseased pre-frontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimers Disease (AD), Frontotemporal Dementia (FTD), and Amyotrophic Lateral Sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 which targeted NF-κB, and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aβ42), phosphorylated Tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel, and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.

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Section: Resultsmentioning

confidence: 99%

Inflammasome-Inhibiting Nanoligomers are Neuroprotective Against Space-Induced Pathology in Healthy and Diseased 3D Human Motor and Pre-Frontal Cortex Brain Organoids

Sharma,

Gilberto,

Rask

et al. 2024

Preprint

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“…Fragmented sleep increases neuronal activity with the consequent excessive release of amyloid ß and amyloid deposition, which increases susceptibility to Alzheimer's disease. The hypoxic/inflammatory stress, interacting with APOEε4, also contributes to increased susceptibility to Alzheimer's disease [25]. In addition to that, amyloid deposition causes injury to sleep/wake centers, leading to sleep fragmentation.…”

Section: Bidirectional Relationship Between Sleep/circadian Rhythms A...mentioning

confidence: 99%

The Bidirectional Relationship between Sleep and Neurodegeneration: Actionability to Improve Brain Health

Ibrahim,

Högl,

Stefani

2024

CTN

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Recently, it has become increasingly clear that there is a bidirectional relationship between sleep/circadian rhythms and neurodegeneration. Knowledge about this topic further improved after the description of the glymphatic system, which is mainly active during sleep. Changes in sleep and circadian rhythms are present not only in overt neurodegenerative diseases but also in their early, prodromal, and preclinical phases, supporting that they precede (and contribute to) the development of neurodegeneration. This narrative review provides a brief overview of sleep and circadian rhythm disruption in neurodegeneration, highlights the bidirectional relationship between sleep changes and neurodegeneration, and addresses future perspectives, in particular, whether sleep changes are able to predict neurodegeneration and the potential sleep actionability to prevent or modulate the development of neurodegenerative diseases.

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“…During the past 20 years, numerous large-scale epidemiological studies have indicated that the presence of an APOE4 allele at the APOE gene locus is associated with an increased individual risk for the development of LOAD (Mamun et al 2020 ; Sun et al 2023 ). In fact, individuals carrying two APOE4 alleles at this gene locus or an APOE3 + APOE4 allele combination have an increased risk for LOAD (Serrano-Pozo et al 2021 ).…”

Section: Apolipoprotein E and Alzheimer’s Diseasementioning

confidence: 99%

Multiple Roles of Apolipoprotein E4 in Oxidative Lipid Metabolism and Ferroptosis During the Pathogenesis of Alzheimer’s Disease

Faraji,

Kühn,

Ahmadian

2024

J Mol Neurosci

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Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide and has a great socio-economic impact. Modified oxidative lipid metabolism and dysregulated iron homeostasis have been implicated in the pathogenesis of this disorder, but the detailed pathophysiological mechanisms still remain unclear. Apolipoprotein E (APOE) is a lipid-binding protein that occurs in large quantities in human blood plasma, and a polymorphism of the APOE gene locus has been identified as risk factors for AD. The human genome involves three major APOE alleles (APOE2, APOE3, APOE4), which encode for three subtly distinct apolipoprotein E isoforms (APOE2, APOE3, APOE4). The canonic function of these apolipoproteins is lipid transport in blood and brain, but APOE4 allele carriers have a much higher risk for AD. In fact, about 60% of clinically diagnosed AD patients carry at least one APOE4 allele in their genomes. Although the APOE4 protein has been implicated in pathophysiological key processes of AD, such as extracellular beta-amyloid (Aβ) aggregation, mitochondrial dysfunction, neuroinflammation, formation of neurofibrillary tangles, modified oxidative lipid metabolism, and ferroptotic cell death, the underlying molecular mechanisms are still not well understood. As for all mammalian cells, iron plays a crucial role in neuronal functions and dysregulation of iron homeostasis has also been implicated in the pathogenesis of AD. Imbalances in iron homeostasis and impairment of the hydroperoxy lipid-reducing capacity induce cellular dysfunction leading to neuronal ferroptosis. In this review, we summarize the current knowledge on APOE4-related oxidative lipid metabolism and the potential role of ferroptosis in the pathogenesis of AD. Pharmacological interference with these processes might offer innovative strategies for therapeutic interventions.

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Roles of ApoE4 on the Pathogenesis in Alzheimer’s Disease and the Potential Therapeutic Approaches

Cited by 23 publications

References 174 publications

Inflammasome-Inhibiting Nanoligomers are Neuroprotective Against Space-Induced Pathology in Healthy and Diseased 3D Human Motor and Pre-Frontal Cortex Brain Organoids

Inflammasome-Inhibiting Nanoligomers are Neuroprotective Against Space-Induced Pathology in Healthy and Diseased 3D Human Motor and Pre-Frontal Cortex Brain Organoids

The Bidirectional Relationship between Sleep and Neurodegeneration: Actionability to Improve Brain Health

Multiple Roles of Apolipoprotein E4 in Oxidative Lipid Metabolism and Ferroptosis During the Pathogenesis of Alzheimer’s Disease

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