Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis

Islam, Sadequl; Sun, Yang; Gao, Yuan; Nakamura, Tomohisa; Noorani, Arshad Ali; Li, Tong; Wong, Philip C.; Kimura, Noriyuki; Matsubara, Etsuro; Kasuga, Kensaku; Ikeuchi, Takeshi; Tomita, Taisuke; Zou, Kun; Michikawa, Makoto

doi:10.1523/jneurosci.2039-21.2021

Cited by 17 publications

(19 citation statements)

References 59 publications

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“…The expression of human PS mutants (PS1ΔE9, PS1G384A, PS1D257A, and PS1D385A) was performed as previously described ( Islam et al, 2022 ). Briefly, the retroviral plasmids were transfected into platinum-E cells using FuGENE (Promega) for retroviral packaging.…”

Section: Methodsmentioning

confidence: 99%

Presenilin Deficiency Increases Susceptibility to Oxidative Damage in Fibroblasts

Zou

Islam

Sun

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a genetic and sporadic neurodegenerative disease characterized by extracellular amyloid-β-protein (Aβ) aggregates as amyloid plaques and neuronal loss in the brain parenchyma of patients. Familial AD (FAD) is found to be genetically linked to missense mutations either in presenilin (PS) or amyloid precursor protein (APP). Most of PS mutations increase Aβ42/Aβ40 ratio, which is thought to result in early amyloid deposition in brain. However, PS deficiency in the fore brain of adult mouse leads to neuronal loss in an Aβ independent manner and the underlying mechanism is largely unknown. In this study, we found that reactive oxygen species (ROS) are increased in PS deficient fibroblasts and that H2O2 and ferrous sulfate treatment produced more ROS in PS deficient fibroblasts than in wild-type fibroblasts. PS deficient fibroblasts showed significantly decreased cellular ferritin levels compared with wild-type fibroblasts, suggesting reduced iron sequestrating capability in PS deficient cells. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ferritin levels, indicating that γ-secretase activity is important for maintaining its levels. Moreover, overexpression PS1 mutants in wild-type fibroblasts decreased ferritin light chain levels and enhanced intracellular ROS levels. Our results suggest that dysfunction of PS may reduce intracellular ferritin levels and is involved in AD pathogenesis through increasing susceptibility to oxidative damage.

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Section: Methodsmentioning

confidence: 99%

Presenilin Deficiency Increases Susceptibility to Oxidative Damage in Fibroblasts

Zou

Islam

Sun

et al. 2022

Front. Aging Neurosci.

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“…APOE has also been shown to be a positive disease modifier in familial AD by a bidirectional PSEN1 interaction. 46 For the first time, recent findings suggest a novel mechanism by which PSEN1 is also involved in AD pathogenesis (Aβ clearance) via regulating apoE secretion. PSEN1 is essential for apoE secretion, and its mutations exert impaired apoE secretion in vitro and in vivo, because decreased γsecretase activity induced by PSEN1 mutations reduces apoE secretion.…”

Section: The Role Of Apoe In Ad Pathophysiologymentioning

confidence: 99%

“…In fact, plasma apoE levels were lower in familial AD patients carrying PSEN1 mutations compared to normal control subjects. 46 The chain of events triggered by various APOE isoforms, as a biological signal, activates specific signaling pathways (as described later) that mediate neuronal dysfunction and accounts for the failure of systems that underlie cognition. 47…”

Section: The Role Of Apoe In Ad Pathophysiologymentioning

confidence: 99%

“…ApoE, Aβ, and plaque formation have recently been linked to a single molecular pathway, through nanoscale lipid compartments. 46,58 ApoE uses astrocyte-derived cholesterol to specifically traffic neuronal APP in and out of lipid clusters, where it interacts with βand γ-secretases to generate Aβ peptides. The association of APP with lipid clusters appears to regulate the amount of Aβ accumulation, and Aβ levels dictate insoluble plaque formation (Figure 3).…”

Section: Apoe and Amyloid Precursor Protein Processingmentioning

confidence: 99%

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Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?

Lozupone

Imbimbo

Balducci

et al. 2022

Alzheimer's & Dementia

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Human apolipoprotein E (apoE) is a 299-amino acid secreted glycoprotein binding cholesterol and phospholipids, and with three common isoforms (APOE ε2, APOE ε3, and APOE ε4). The exact mechanism by which APOE gene variants increase/decrease Alzheimer's disease (AD) risk is not fully understood, but APOE isoforms differently affect brain homeostasis and neuroinflammation, blood-brain barrier (BBB) permeability, glial function, synaptogenesis, oral/gut microbiota, neural networks, amyloid beta (Aβ) deposition, and tau-mediated neurodegeneration. In this perspective, we propose a comprehensive interpretation of APOE-mediated effects within AD pathophysiology, describing some specific cellular, biochemical, and epigenetic mechanisms and updating the different APOE-targeting approaches being developed as potential AD therapies. Intracisternal adeno-associated viral-mediated delivery of APOE ε2 is being tested in AD APOE ε4/ε4 carriers, while APOE mimetics are being used in subjects with perioperative neurocognitive disorders. Other approaches including APOE

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“…It was recently observed that ApoE secretion is regulated by presenilin (PS) [ 80 ], is completely abolished in PS-deficient cells, and markedly decreased by the inhibition of gamma-secretase activity.…”

Section: Where Does Brain Iron Excess Come From?mentioning

confidence: 99%

Iron Deposition in Brain: Does Aging Matter?

Ficiarà

Stura

Guiot

2022

IJMS

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The alteration of iron homeostasis related to the aging process is responsible for increased iron levels, potentially leading to oxidative cellular damage. Iron is modulated in the Central Nervous System in a very sensitive manner and an abnormal accumulation of iron in the brain has been proposed as a biomarker of neurodegeneration. However, contrasting results have been presented regarding brain iron accumulation and the potential link with other factors during aging and neurodegeneration. Such uncertainties partly depend on the fact that different techniques can be used to estimate the distribution of iron in the brain, e.g., indirect (e.g., MRI) or direct (post-mortem estimation) approaches. Furthermore, recent evidence suggests that the propensity of brain cells to accumulate excessive iron as a function of aging largely depends on their anatomical location. This review aims to collect the available data on the association between iron concentration in the brain and aging, shedding light on potential mechanisms that may be helpful in the detection of physiological neurodegeneration processes and neurodegenerative diseases such as Alzheimer’s disease.

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Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis

Cited by 17 publications

References 59 publications

Presenilin Deficiency Increases Susceptibility to Oxidative Damage in Fibroblasts

Presenilin Deficiency Increases Susceptibility to Oxidative Damage in Fibroblasts

Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?

Iron Deposition in Brain: Does Aging Matter?

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