scholarly journals Lipid rafts act as a common platform for Aß oligomer-induced Alzheimer’s pathology

2021 ◽  
Author(s):  
Takeshi Kawarabayashi ◽  
Takumi Nakamura ◽  
Kaoru Sato ◽  
Yusuke Seino ◽  
Sadanobu Ichii ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Glycogen Synthase ◽  
Cellular Prion Protein ◽  
Phosphorylated Tau ◽  
Aspartate Receptor ◽  
Temporal Relationships ◽  
Alzheimer’S Pathology ◽  
Pathological Event ◽  
Tg2576 Mice ◽  
Common Platform

Abstract Background Amyloid ß protein (Aß) oligomers induce the overproduction of phosphorylated tau and neurodegeneration. These cascades gradually cause cognitive impairment in Alzheimer’s disease (AD). While each pathological event in AD has been studied in detail separately, the spatial and temporal relationships between pathological events in AD remain unclear. Here, we demonstrated that lipid rafts function as a common platform for the pathological cascades of AD. Methods Cellular and synaptosomal lipid rafts were prepared from the brains of Aß amyloid model mice (Tg2576 mice) and double transgenic mice (Tg2576 x TgTauP301L mice) and longitudinally analyzed. Results Aß oligomers, the cellular prion protein (PrPc), and Aß oligomer/PrPc complexes were detected in the lipid rafts. The levels of Fyn, the phosphorylated NR2B subunit of the N-methyl-D-aspartate receptor, glycogen synthase kinase 3 beta, total tau, phosphorylated tau, and tau oligomers increased with Aß oligomer accumulation in both the cellular and synaptosomal lipid rafts. Increases in the levels of these molecules were first seen at 6 months of age and corresponded with the early stages of Aß accumulation in the amyloid model mice. Conclusions Lipid rafts act as a common platform for the progression of Alzheimer’s pathology. The findings of this study suggest a novel therapeutic approach to AD, involving the modification of lipid raft components and the inhibition of their roles in the sequential pathological events of AD.

P3-313: Copper induces accumulation of tau and phosphorylated tau in lipid rafts

2006 ◽  
Vol 2 ◽  
pp. S467-S467
Author(s):  
Elysia L. Robb ◽  
Ya Hui Hung ◽  
Irene Volitakis ◽  
Robert Cherny ◽  
Ashley I. Bush
Keyword(s):  
Lipid Rafts ◽  
Phosphorylated Tau

scholarly journals Lipid Rafts: Linking Alzheimer's Amyloid-βProduction, Aggregation, and Toxicity at Neuronal Membranes

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Jo V. Rushworth ◽  
Nigel M. Hooper
Keyword(s):  
Glutamate Receptors ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Cell Signalling ◽  
Cellular Prion Protein ◽  
Membrane Microdomains ◽  
Synaptic Dysfunction ◽  
Memory Impairments ◽  
Neuronal Membranes ◽  
Neuronal Functions

Lipid rafts are membrane microdomains, enriched in cholesterol and sphingolipids, into which specific subsets of proteins and lipids partition, creating cell-signalling platforms that are vital for neuronal functions. Lipid rafts play at least three crucial roles in Alzheimer's Disease (AD), namely, in promoting the generation of the amyloid-β(Aβ) peptide, facilitating its aggregation upon neuronal membranes to form toxic oligomers and hosting specific neuronal receptors through which the AD-related neurotoxicity and memory impairments of the Aβoligomers are transduced. Recent evidence suggests that Aβoligomers may exert their deleterious effects through binding to, and causing the aberrant clustering of, lipid raft proteins including the cellular prion protein and glutamate receptors. The formation of these pathogenic lipid raft-based platforms may be critical for the toxic signalling mechanisms that underlie synaptic dysfunction and neuropathology in AD.

scholarly journals Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth

2005 ◽  
Vol 169 (2) ◽  
pp. 341-354 ◽  
Author(s):  
Antonella Santuccione ◽  
Vladimir Sytnyk ◽  
Iryna Leshchyns'ka ◽  
Melitta Schachner
Keyword(s):  
Neurite Outgrowth ◽  
Lipid Rafts ◽  
Prion Protein ◽  
System Development ◽  
Neuronal Cell ◽  
Neural Cell ◽  
Nervous System Development ◽  
Cellular Prion Protein ◽  
Promote Neurite Outgrowth ◽  
Cis And Trans

In spite of advances in understanding the role of the cellular prion protein (PrP) in neural cell interactions, the mechanisms of PrP function remain poorly characterized. We show that PrP interacts directly with the neural cell adhesion molecule (NCAM) and associates with NCAM at the neuronal cell surface. Both cis and trans interactions between NCAM at the neuronal surface and PrP promote recruitment of NCAM to lipid rafts and thereby regulate activation of fyn kinase, an enzyme involved in NCAM-mediated signaling. Cis and trans interactions between NCAM and PrP promote neurite outgrowth. When these interactions are disrupted in NCAM-deficient and PrP-deficient neurons or by PrP antibodies, NCAM/PrP-dependent neurite outgrowth is arrested, indicating that PrP is involved in nervous system development cooperating with NCAM as a signaling receptor.

scholarly journals The Present State of Lithium for the Prevention of Dementia Related to Alzheimer’s Dementia in Clinical and Epidemiological Studies: A Critical Review

2021 ◽  
Vol 18 (15) ◽  
pp. 7756
Author(s):  
Nobuyoshi Ishii ◽  
Takeshi Terao ◽  
Hirofumi Hirakawa
Keyword(s):  
Bipolar Disorder ◽  
Present State ◽  
Critical Review ◽  
Clinical Studies ◽  
Clinical Evidence ◽  
Glycogen Synthase ◽  
Epidemiological Studies ◽  
Glycogen Synthase Kinase 3 ◽  
Phosphorylated Tau ◽  
Dementia Prevention

Despite the unavailability of essential anti-dementia drugs, lithium may inhibit glycogen synthase kinase-3 (GSK-3) and decrease beta-amyloid and hyper-phosphorylated tau. In this review, we hypothesized that trace to standard levels of lithium (i.e., corresponding to the therapeutic levels for bipolar disorder) may be effective for dementia prevention. Excluding three insufficient level studies, we obtained two and one excellent clinical studies on standard and trace lithium levels, respectively, all of which supported the effects of lithium for dementia prevention. In addition, we identified good clinical and epidemiological studies (four each) on standard lithium levels, of which six studies supported the effects of lithium. Moreover, of three good epidemiological studies on trace lithium levels, two supported the aforementioned effects of lithium. The number of studies were substantially small, particularly those on trace lithium levels. Moreover, studies on standard lithium levels were insufficient to establish the efficacy of lithium for dementia prevention. This necessitates accumulating good or excellent clinical evidence for the effects of trace to standard lithium levels on dementia prevention.

scholarly journals Endogenous Brain Lipids Inhibit Prion Amyloid Formation In Vitro

2017 ◽  
Vol 91 (9) ◽  
Author(s):  
Clare E. Hoover ◽  
Kristen A. Davenport ◽  
Davin M. Henderson ◽  
Mark D. Zabel ◽  
Edward A. Hoover
Keyword(s):  
Real Time ◽  
Lipid Rafts ◽  
Prion Protein ◽  
Polar Lipid ◽  
Cellular Prion Protein ◽  
Conversion Process ◽  
Amyloid Formation ◽  
Inhibitory Function ◽  
Prion Conversion

ABSTRACT The normal cellular prion protein (PrPC) resides in detergent-resistant outer membrane lipid rafts in which conversion to the pathogenic misfolded form is believed to occur. Once misfolding occurs, the pathogenic isoform polymerizes into highly stable amyloid fibrils. In vitro assays have demonstrated an intimate association between prion conversion and lipids, specifically phosphatidylethanolamine, which is a critical cofactor in the formation of synthetic infectious prions. In the current work, we demonstrate an alternative inhibitory function of lipids in the prion conversion process as assessed in vitro by real-time quaking-induced conversion (RT-QuIC). Using an alcohol-based extraction technique, we removed the lipid content from chronic wasting disease (CWD)-infected white-tailed deer brain homogenates and found that lipid extraction enabled RT-QuIC detection of CWD prions in a 2-log10-greater concentration of brain sample. Conversely, addition of brain-derived lipid extracts to CWD prion brain or lymph node samples inhibited amyloid formation in a dose-dependent manner. Subsequent lipid analysis demonstrated that this inhibitory function was restricted to the polar lipid fraction in brain. We further investigated three phospholipids commonly found in lipid membranes, phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol, and found all three similarly inhibited RT-QuIC. These results demonstrating polar-lipid, and specifically phospholipid, inhibition of prion-seeded amyloid formation highlight the diverse roles lipid constituents may play in the prion conversion process. IMPORTANCE Prion conversion is likely influenced by lipid interactions, given the location of normal prion protein (PrPC) in lipid rafts and lipid cofactors generating infectious prions in in vitro models. Here, we use real-time quaking-induced conversion (RT-QuIC) to demonstrate that endogenous brain polar lipids can inhibit prion-seeded amyloid formation, suggesting that prion conversion is guided by an environment of proconversion and anticonversion lipids. These experiments also highlight the applicability of RT-QuIC to identify potential therapeutic inhibitors of prion conversion.

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