Amyloid-β Interactions with Lipid Rafts in Biomimetic Systems: A Review of Laboratory Methods

2020 ◽  
pp. 47-86
Author(s):  
Galya Staneva ◽  
Chiho Watanabe ◽  
Nicolas Puff ◽  
Vesela Yordanova ◽  
Michel Seigneuret ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Amyloid Β ◽  
Laboratory Methods ◽  
Biomimetic Systems

scholarly journals Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model

2021 ◽  
Vol 22 (22) ◽  
pp. 12181
Author(s):  
Guido Santos ◽  
Mario Díaz
Keyword(s):  
Alzheimer’S Disease ◽  
Mathematical Model ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Lipid Rafts ◽  
Brain Cortex ◽  
Clinical Symptoms ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Human Brain Cortex

Alzheimer’s disease (AD) is a neurodegenerative disease caused by abnormal functioning of critical physiological processes in nerve cells and aberrant accumulation of protein aggregates in the brain. The initial cause remains elusive—the only unquestionable risk factor for the most frequent variant of the disease is age. Lipid rafts are microdomains present in nerve cell membranes and they are known to play a significant role in the generation of hallmark proteinopathies associated to AD, namely senile plaques, formed by aggregates of amyloid β peptides. Recent studies have demonstrated that human brain cortex lipid rafts are altered during early neuropathological phases of AD as defined by Braak and Braak staging. The lipid composition and physical properties of these domains appear altered even before clinical symptoms are detected. Here, we use a coarse grain molecular dynamics mathematical model to predict the dimensional evolution of these domains using the experimental data reported by our group in human frontal cortex. The model predicts significant size and frequency changes which are detectable at the earliest neuropathological stage (ADI/II) of Alzheimer’s disease. Simulations reveal a lower number and a larger size in lipid rafts from ADV/VI, the most advanced stage of AD. Paralleling these changes, the predictions also indicate that non-rafts domains undergo simultaneous alterations in membrane peroxidability, which support a link between oxidative stress and AD progression. These synergistic changes in lipid rafts dimensions and non-rafts peroxidability are likely to become part of a positive feedback loop linked to an irreversible amyloid burden and neuronal death during the evolution of AD neuropathology.

scholarly journals Amyloidogenic Processing of APP in Lipid Rafts

2010 ◽  
Vol 3 (1) ◽  
pp. 21-31
Author(s):  
Madepalli K. Lakshmana ◽  
Subhojit Roy ◽  
Kaihong Mi ◽  
David E. Kang
Keyword(s):  
Lipid Rafts ◽  
Lipid Raft ◽  
Amyloid Β ◽  
Convincing Evidence ◽  
Amyloid Β Peptide ◽  
Cholesterol Levels ◽  
Amyloidogenic Processing ◽  
Secretase Inhibitor ◽  
Aβ Generation ◽  
Lipid Raft Microdomains

Increased generation of amyloid β peptide (Aβ) derived from amyloid precursor protein (APP) is the primary pathological characteristic of Alzheimer’s disease (AD). However, the sub cellular compartment in which APP undergoes cleavage by secretases to generate Aβ is not precisely known. Compelling evidences suggest that amyloidogenic processing of APP occurs in lipid rafts. An indirect support for lipid raft processing of APP includes the localization of Aβ, APP C-terminal fragments (CTFs), APP holoprotein and secretases in the lipid raft microdomains, although few studies failed to find APP in the lipid rafts. The indirect support also comes from both experimental and clinical studies involving modulation of cholesterol levels and its effect on Aβ generation. Moderate depletion of cholesterol results in significant reduction in Aβ levels and increased dietary intake of cholesterol leads to higher levels of Aβ production suggesting that amyloidogenic processing of APP strongly depends on cholesterol levels and therefore on lipid raft integrity. More convincing evidence that lipid rafts are critical for amyloidogenic processing of APP comes from studies using antibody-mediated co-patching of APP and BACE1 which results in lipid raft association of APP and BACE1 and increased Aβ generation. Further, an endosome/lipid raft targeting of β-secretase inhibitor by sterol-mediated anchoring leading to reduced Aβ generation also suggests that lipid rafts are pivotal for amyloidogenic processing of APP. In the absence of an effective therapy for AD, proteins responsible for delivery of APP to lipid rafts including LRP, RanBP9 and ApoER2 may be excellent therapeutic targets in AD.

Amyloid β oligomerization is induced by brain lipid rafts

2006 ◽  
Vol 99 (3) ◽  
pp. 878-889 ◽  
Author(s):  
Sang-Il Kim ◽  
Jae-Sung Yi ◽  
Young-Gyu Ko
Keyword(s):  
Lipid Rafts ◽  
Amyloid Β ◽  
Brain Lipid

scholarly journals Prion Protein-mediated Toxicity of Amyloid-β Oligomers Requires Lipid Rafts and the Transmembrane LRP1

2013 ◽  
Vol 288 (13) ◽  
pp. 8935-8951 ◽  
Author(s):  
Jo V. Rushworth ◽  
Heledd H. Griffiths ◽  
Nicole T. Watt ◽  
Nigel M. Hooper
Keyword(s):  
Lipid Rafts ◽  
Prion Protein ◽  
Amyloid Β

scholarly journals GD3 Accumulation in Cell Surface Lipid Rafts Prior to Mitochondrial Targeting Contributes to Amyloid-β-induced Apoptosis

2010 ◽  
Vol 25 (10) ◽  
pp. 1492 ◽  
Author(s):  
Jong-Kook Kim ◽  
Sang-Ho Kim ◽  
Hee-Young Cho ◽  
Hee-Soo Shin ◽  
Hye-Ryen Sung ◽  
...  
Keyword(s):  
Cell Surface ◽  
Lipid Rafts ◽  
Amyloid Β ◽  
Surface Lipid ◽  
Mitochondrial Targeting ◽  
Induced Apoptosis

scholarly journals BECN1/Beclin 1 is recruited into lipid rafts by prion to activate autophagy in response to amyloid β 42

Autophagy ◽  
2013 ◽  
Vol 9 (12) ◽  
pp. 2009-2021 ◽  
Author(s):  
Jihoon Nah ◽  
Jong-Ok Pyo ◽  
Sunmin Jung ◽  
Seung-Min Yoo ◽  
Tae-In Kam ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Amyloid Β ◽  
Beclin 1

scholarly journals Binding of Amyloid β(1–42)-Calmodulin Complexes to Plasma Membrane Lipid Rafts in Cerebellar Granule Neurons Alters Resting Cytosolic Calcium Homeostasis

2021 ◽  
Vol 22 (4) ◽  
pp. 1984
Author(s):  
Joana Poejo ◽  
Jairo Salazar ◽  
Ana M. Mata ◽  
Carlos Gutierrez-Merino
Keyword(s):  
Lipid Rafts ◽  
Calcium Homeostasis ◽  
Binding Capacity ◽  
Primary Cultures ◽  
Amyloid Β ◽  
Cytosolic Calcium ◽  
Cerebellar Granule Neurons ◽  
Granule Neurons ◽  
Microscopy Imaging ◽  
Cerebellar Granule

Lipid rafts are a primary target in studies of amyloid β (Aβ) cytotoxicity in neurons. Exogenous Aβ peptides bind to lipid rafts, which in turn play a key role in Aβ uptake, leading to the formation of neurotoxic intracellular Aβ aggregates. On the other hand, dysregulation of intracellular calcium homeostasis in neurons has been observed in Alzheimer’s disease (AD). In a previous work, we showed that Aβ(1–42), the prevalent Aβ peptide found in the amyloid plaques of AD patients, binds with high affinity to purified calmodulin (CaM), with a dissociation constant ≈1 nM. In this work, to experimentally assess the Aβ(1–42) binding capacity to intracellular CaM, we used primary cultures of mature cerebellar granule neurons (CGN) as a neuronal model. Our results showed a large complexation of submicromolar concentrations of Aβ(1–42) dimers by CaM in CGN, up to 120 ± 13 picomoles of Aβ(1–42) /2.5 × 106 cells. Using fluorescence microscopy imaging, we showed an extensive co-localization of CaM and Aβ(1–42) in lipid rafts in CGN stained with up to 100 picomoles of Aβ(1–42)-HiLyteTM-Fluor555 monomers. Intracellular Aβ(1–42) concentration in this range was achieved by 2 h incubation of CGN with 2 μM Aβ(1–42), and this treatment lowered the resting cytosolic calcium of mature CGN in partially depolarizing 25 mM potassium medium. We conclude that the primary cause of the resting cytosolic calcium decrease is the inhibition of L-type calcium channels of CGN by Aβ(1–42) dimers, whose activity is inhibited by CaM:Aβ(1–42) complexes bound to lipid rafts.

scholarly journals Amyloid Oligomer Neurotoxicity, Calcium Dysregulation, and Lipid Rafts

2011 ◽  
Vol 2011 ◽  
pp. 1-17 ◽  
Author(s):  
Fiorella Malchiodi-Albedi ◽  
Silvia Paradisi ◽  
Andrea Matteucci ◽  
Claudio Frank ◽  
Marco Diociaiuti
Keyword(s):  
Lipid Rafts ◽  
Protein Misfolding ◽  
Large Body ◽  
Amyloid Β ◽  
Misfolded Proteins ◽  
Transmissible Spongiform Encephalopathies ◽  
Amyloid Proteins ◽  
Spongiform Encephalopathies ◽  
Amyloidogenic Processing ◽  
High Propensity

Amyloid proteins constitute a chemically heterogeneous group of proteins, which share some biophysical and biological characteristics, the principal of which are the high propensity to acquire an incorrect folding and the tendency to aggregate. A number of diseases are associated with misfolding and aggregation of proteins, although only in some of them—most notably Alzheimer's disease (AD) and transmissible spongiform encephalopathies (TSEs)—a pathogenetic link with misfolded proteins is now widely recognized. Lipid rafts (LRs) have been involved in the pathophysiology of diseases associated with protein misfolding at several levels, including aggregation of misfolded proteins, amyloidogenic processing, and neurotoxicity. Among the pathogenic misfolded proteins, the AD-related protein amyloid β (Aβ) is by far the most studied protein, and a large body of evidence has been gathered on the role played by LRs in Aβ pathogenicity. However, significant amount of data has also been collected for several other amyloid proteins, so that their ability to interact with LRs can be considered an additional, shared feature characterizing the amyloid protein family. In this paper, we will review the evidence on the role of LRs in the neurotoxicity of huntingtin, α-synuclein, prion protein, and calcitonin.

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