Neuronal ROS-Induced Glial Lipid Droplet Formation is Altered by Loss of Alzheimer's Disease-Associated Genes

Moulton, Matthew J.; Barish, Scott; Ralhan, Isha; Chang, Jinlan; Goodman, Lindsey D.; Harland, Jake G.; Marcogliese, Paul C.; Johansson, Jan; Ioannou, Maria S.; Bellen, Hugo J.

doi:10.2139/ssrn.3811838

Cited by 3 publications

(5 citation statements)

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“…This study further supports the connection between ApoE regulation of brain LD metabolism and AD pathogenesis. In addition to ApoE, other AD risk factor genes such as ABCA1 , ABCA7, and PICALM are also involved in the formation of glial LDs [185]. Collectively, these studies suggest that impairment in lipid clearance and transport could underlie lipid dyshomeostasis and reduced neurotrophic function observed in aging and AD brains.…”

Section: Deciphering Lipid Metabolism In Ad: Mechanistic Linksmentioning

confidence: 99%

Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise

Yin

2022

The FEBS Journal

135

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Alzheimer’s disease (AD) is an age‐associated neurodegenerative disorder with multifactorial etiology, intersecting genetic and environmental risk factors, and a lack of disease‐modifying therapeutics. While the abnormal accumulation of lipids was described in the very first report of AD neuropathology, it was not until recent decades that lipid dyshomeostasis became a focus of AD research. Clinically, lipidomic and metabolomic studies have consistently shown alterations in the levels of various lipid classes emerging in early stages of AD brains. Mechanistically, decades of discovery research have revealed multifaceted interactions between lipid metabolism and key AD pathogenic mechanisms including amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, and myelin degeneration. In the present review, converging evidence defining lipid dyshomeostasis in AD is summarized, followed by discussions on mechanisms by which lipid metabolism contributes to pathogenesis and modifies disease risk. Furthermore, lipid‐targeting therapeutic strategies, and the modification of their efficacy by disease stage, ApoE status, and metabolic and vascular profiles, are reviewed.

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Section: Deciphering Lipid Metabolism In Ad: Mechanistic Linksmentioning

confidence: 99%

Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise

Yin

2022

The FEBS Journal

135

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“…Since there is no ABCA1 ortholog in Drosophila with clear homology and there are 10 ATP binding cassette transporters from the ABCA family, candidate fly lines were tested as previously described 40 . RNAi targeting ABCA3 clearly enhanced the REP, similarly to other mitophagy-promoting manipulations.…”

Section: Resultsmentioning

confidence: 99%

AI-guided screen identifies probucol-mediated mitophagy enhancement through modulation of lipid droplets

Moskal

Visanji

Gorbenko

et al. 2022

Preprint

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Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated under basal conditions by probucol treatment in addition to increased contact between lipid droplets and mitochondria. Conversely, lipid droplet expansion, which occurs following mitochondrial damage was suppressed by probucol and probucol-mediated mitophagy enhancement required lipid droplets. Probucol-mediated lipid droplet dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage.

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“…Much data have accumulated to indicate that mitochondrial dysfunction, especially at the level of Complex I, accumulates with age, leading to the production of ROS and the reduced production of ATP building blocks, which prevents the necessary work for the maintenance of cells and organs. The synthesis of lipids at the neuronal level can be induced by the accumulation of high levels of reactive oxygen species (ROS) [ 88 , 89 ]. Peroxidized lipids are sequestered in the lipid droplets (LD) at the glial level, delaying neurotoxicity.…”

Section: From Vascular Damage To Alteration Of Metabolismmentioning

confidence: 99%

“…The synthesized lipids undergo the peroxidation process thanks to the presence of ROS. They are subsequently transferred to the pigment glia, where they are sequestered in the LDs [ 88 ]. Activation of neuronal lipogenesis, in the absence of ROS, determines the formation of LD but does not lead to neurodegeneration [ 90 ].…”

Section: From Vascular Damage To Alteration Of Metabolismmentioning

confidence: 99%

“…When ROS levels rise, the peroxidized lipids are no longer able to be exported and transferred to the glial cell LDs. This determines neuronal damage [ 88 ]. In a mouse model of human APOE expression [ 100 , 101 ], an ABCA1 agonist peptide was able to restore APOE4 lipidation and improve Aβ42/tau pathologies.…”

Section: From Vascular Damage To Alteration Of Metabolismmentioning

confidence: 99%

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Alzheimer’s Disease from the Amyloidogenic Theory to the Puzzling Crossroads between Vascular, Metabolic and Energetic Maladaptive Plasticity

et al. 2023

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Alzheimer’s disease (AD) is a progressive and degenerative disease producing the most common type of dementia worldwide. The main pathogenetic hypothesis in recent decades has been the well-known amyloidogenic hypothesis based on the involvement of two proteins in AD pathogenesis: amyloid β (Aβ) and tau. Amyloid deposition reported in all AD patients is nowadays considered an independent risk factor for cognitive decline. Vascular damage and blood–brain barrier (BBB) failure in AD is considered a pivotal mechanism for brain injury, with increased deposition of both immunoglobulins and fibrin. Furthermore, BBB dysfunction could be an early sign of cognitive decline and the early stages of clinical AD. Vascular damage generates hypoperfusion and relative hypoxia in areas with high energy demand. Long-term hypoxia and the accumulation within the brain parenchyma of neurotoxic molecules could be seeds of a self-sustaining pathological progression. Cellular dysfunction comprises all the elements of the neurovascular unit (NVU) and neuronal loss, which could be the result of energy failure and mitochondrial impairment. Brain glucose metabolism is compromised, showing a specific region distribution. This energy deficit worsens throughout aging. Mild cognitive impairment has been reported to be associated with a glucose deficit in the entorhinal cortex and in the parietal lobes. The current aim is to understand the complex interactions between amyloid β (Aβ) and tau and elements of the BBB and NVU in the brain. This new approach aimed at the study of metabolic mechanisms and energy insufficiency due to mitochondrial impairment would allow us to define therapies aimed at predicting and slowing down the progression of AD.

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Neuronal ROS-Induced Glial Lipid Droplet Formation is Altered by Loss of Alzheimer's Disease-Associated Genes

Cited by 3 publications

References 0 publications

Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise

Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise

AI-guided screen identifies probucol-mediated mitophagy enhancement through modulation of lipid droplets

Alzheimer’s Disease from the Amyloidogenic Theory to the Puzzling Crossroads between Vascular, Metabolic and Energetic Maladaptive Plasticity

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