The Role of Lipids and Membranes in the Pathogenesis of Alzheimer's Disease: A Comprehensive View

Penke, Botond; Paragi, Gábor; Gera, János; Berkecz, Róbert; Kovács, Zsolt; Crul, Tim; Vı́gh, László

doi:10.2174/1567205015666180911151716

Cited by 46 publications

(32 citation statements)

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“…We anticipate that the most valuable feature of Fluopack will be its ability to reveal subcellular phenotypes easily missed by other methods, such as changes in lipid trafficking inside the cell, or variations in the concentration of ions in specific organelles. Growing evidence suggests that dysregulation of lipid metabolism occurs in diseases such as Alzheimer's 10 and Parkinson's disease 11 . This type of alteration had been mostly overlooked so far, for lack of convenient tools to enable their study.…”

mentioning

confidence: 99%

Fluopack screening platform for unbiased cellular phenotype profiling

Zhao

Moutsatsos

Moretti

et al. 2020

Sci Rep

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Beat nyfeler 2 & christophe Antczak 1* Gene and compound functions are often interrogated by perturbation. However, we have limited methods to capture associated phenotypes in an unbiased and holistic manner. Here, we describe Fluopack screening as a novel platform enabling the profiling of subcellular phenotypes associated with perturbation. Our approach leverages imaging of a panel of fluorescent chemical probes to survey cellular processes in an unbiased and high throughput fashion. Segmentation-free, whole image analysis applied to Fluopack images identifies probes revealing distinct phenotypes upon perturbation, thereby informing on the function and mechanism of action of perturbagens. this chemical biology approach allows to interrogate phenotypes that tend to be overlooked by other methods, such as lipid trafficking and ion concentration inside the cell. Fluopack screening is a powerful approach to study orphan protein function, as exemplified by the characterization of TMEM41B as novel regulator of lipid mobilization.

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mentioning

confidence: 99%

Fluopack screening platform for unbiased cellular phenotype profiling

Zhao

Moutsatsos

Moretti

et al. 2020

Sci Rep

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“…On the other hand, PNSs may arise from endogenous sources. These can be the result of lipid dysregulation involving lipoproteins such as ApoE ε4, which is a known genetic risk factor for AD (Potter and Wisniewski, 2012), or membrane components such as cholesterol, gangliosides and GAGs (Iannuzzi et al, 2015;Penke et al, 2018). Furthermore, membrane fragment microparticles from brain injury (Zhao et al, 2017) can potentially act as catalytic surfaces for HEN mediated amyloid aggregation in traumatic brain injury.…”

Section: A Mechanistic Approach To Etiologymentioning

confidence: 99%

Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

et al. 2020

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Amyloids are fibrillar protein aggregates associated with diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes and Creutzfeldt-Jakob disease. The process of amyloid polymerization involves three pathological protein transformations; from natively folded conformation to the cross-β conformation, from biophysically soluble to insoluble, and from biologically functional to non-functional. While amyloids share a similar cross-β conformation, the biophysical transformation can either take place spontaneously via a homogeneous nucleation mechanism (HON) or catalytically on an exogenous surface via a heterogeneous nucleation mechanism (HEN). Here, we postulate that the different nucleation pathways can serve as a mechanistic basis for an etiological classification of amyloidopathies, where hereditary forms generally follow the HON pathway, while sporadic forms follow seed-induced (prions) or surface-induced (including microbially induced) HEN pathways. Critically, the conformational and biophysical amyloid transformation results in loss-of-function (LOF) of the original natively folded and soluble protein. This LOF can, at least initially, be the mechanism of amyloid toxicity even before amyloid accumulation reaches toxic levels. By highlighting the important role of non-protein species in amyloid formation and LOF mechanisms of toxicity, we propose a generalized mechanistic framework that could help better understand the diverse etiology of amyloid diseases and offer new opportunities for therapeutic interventions, including replacement therapies.

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“…[95] The behavior of A peptides in vivo in the presence of cholesterol is complex to disentangle, not least because cholesterol levels change with cellular location, age, disease, and under the influence of some medications. [96] Cholesterol levels also affect the activity of -secretases [97][98][99] and the distribution of APP. [100] In diseased brains, the cholesterol content of the temporal gyrus is significantly reduced when compared with non-diseased brains.…”

Section: Box 1: the Role Of Membranes In A Fibrillogenesismentioning

confidence: 99%

Far from Inert: Membrane Lipids Possess Intrinsic Reactivity That Has Consequences for Cell Biology

Sanderson

2020

BioEssays

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In this article, it is hypothesized that a fundamental chemical reactivity exists between some non‐lipid constituents of cellular membranes and ester‐based lipids, the significance of which is not generally recognized. Many peptides and smaller organic molecules have now been shown to undergo lipidation reactions in model membranes in circumstances where direct reaction with the lipid is the only viable route for acyl transfer. Crucially, drugs like propranolol are lipidated in vivo with product profiles that are comparable to those produced in vitro. Some compounds have also been found to promote lipid hydrolysis. Drugs with high lytic activity in vivo tend to have higher toxicity in vitro. Deacylases and lipases are proposed as key enzymes that protect cells against the effects of intrinsic lipidation. The toxic effects of intrinsic lipidation are hypothesized to include a route by which nucleation can occur during the formation of amyloid fibrils.

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The Role of Lipids and Membranes in the Pathogenesis of Alzheimer's Disease: A Comprehensive View

Cited by 46 publications

References 0 publications

Fluopack screening platform for unbiased cellular phenotype profiling

Fluopack screening platform for unbiased cellular phenotype profiling

Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

Far from Inert: Membrane Lipids Possess Intrinsic Reactivity That Has Consequences for Cell Biology

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