Biophysical alterations in lipid rafts from human cerebral cortex associate with increased BACE1/APP interaction in early stages of Alzheimer's disease

In the present study, we have assessed the biophysical properties of lipid rafts from different brain areas in subjects exhibiting early neuropathological stages of Alzheimer's disease (AD). By means of steady-state fluorescence polarization analyses using two environment-sensitive fluorescent probes, we demonstrate that lipid rafts from cerebellum, and frontal and entorhinal cortices, exhibit different biophysical behaviors depending on the stage of the disease. Thus, while membrane anisotropies were similar in the cerebellum along stages, lipid rafts from frontal and entorhinal cortices at AD stages I/II and AD III were significantly more liquid-ordered than in control subjects, both at the aqueous interface and hydrophobic core of the raft membrane. Thermotropic analyses demonstrated the presence of Arrhenius breakpoints between 28.3-32.0 °C, which were not influenced by the disease stage. However, analyses of membrane microviscosity (ηapp) demonstrate that frontal and entorhinal lipid rafts are notably more viscous and liquid-ordered all across the membrane from early stages of the disease. These physicochemical alterations in lipid rafts do not correlate with changes in cholesterol or sphingomyelin levels, but to reduced unsaturation index and increased saturate/polyunsaturated ratios in phospholipid acyl chains. Moreover, we demonstrate that β-secretase/AβPP (amyloid-β protein precursor) interaction and lipid raft microviscosity are strongly, and positively, correlated in AD frontal and entorhinal cortices. These observations strengthens the hypothesis that physical properties of these microdomains modulate the convergence of amyloidogenic machinery toward lipid rafts, and also points to a critical role of polyunsaturated fatty acids in amyloidogenic processing of AβPP

Lipid raft aging in the human frontal cortex during nonpathological aging: gender influences and potential implications in Alzehimer's disease

Lipid rafts are highly dynamic membrane domains featured by distinctive biochemical composition and physicochemical properties compared with the surrounding plasma membrane. These microstructures are associated not only with cellular signaling and communication in normal nerve cells but also with pathological processing of amyloid precursor protein in Alzheimer's disease. Using lipid rafts isolated from human frontal cortex in nondemented subjects aging 24 to 85 years, we demonstrate here that lipid structure of lipid rafts undergo significant alterations of specific lipid classes and phospholipid-bound fatty acids as brain cortex correlating with aging. Main changes affect levels of plasmalogens, polyunsaturated fatty acids (especially docosahexaenoic acid and arachidonic acid), total polar lipids (mainly phosphatidylinositol, sphingomyelin, sulfatides, and cerebrosides), and total neutral lipids (particularly cholesterol and sterol esters). Besides, relevant relationships between main fatty acids and/or lipid classes were altered in an age-related manner. This 'lipid raft aging' exhibits clear gender differences and appear to be more pronounced in women than in men, especially in older (postmenopausal) women. The outcomes led us to conclude that human cortical lipid rafts are modified by aging in a gender-dependent fashion. Given the central role of bilayer lipid matrix in lipid rafts functionality and neuronal signaling, we hypothesize that these findings might underlie the higher prevalence of cognitive decline evolving toward Alzheimer's disease in postmenopausal women

Lipid alterations in lipid rafts from alzheimer's disease human brain cortex

Lipid rafts are membrane microdomains intimately associated with cell signaling. These biochemical microstructures are characterized by their high contents of sphingolipids, cholesterol and saturated fatty acids and a reduced content of polyunsaturated fatty acids (PUFA). Here, we have purified lipid rafts of human frontal brain cortex from normal and Alzheimer's disease (AD) and characterized their biochemical lipid composition. The results revealed that lipid rafts from AD brains exhibit aberrant lipid profiles compared to healthy brains. In particular, lipid rafts from AD brains displayed abnormally low levels of n-3 long chain polyunsaturated fatty acids (LCPUFA, mainly 22:6n-3, docosahexaenoic acid) and monoenes (mainly 18:1n-9, oleic acid), as well as reduced unsaturation and peroxidability indexes. Also, multiple relationships between phospholipids and fatty acids were altered in AD lipid rafts. Importantly, no changes were observed in the mole percentage of lipid classes and fatty acids in rafts from normal brains throughout the lifespan (24-85 years). These indications point to the existence of homeostatic mechanisms preserving lipid raft status in normal frontal cortex. The disruption of such mechanisms in AD brains leads to a considerable increase in lipid raft order and viscosity, which may explain the alterations in lipid raft signaling observed in AD

Anomalies occurring in lipid profiles and protein distribution in frontal cortex lipid rafts in dementia with Lewy bodies disclose neurochemical traits partially shared by Alzheimer's and Parkinson's diseases

Lipid rafts are highly dynamic membrane microdomains intimately associated with cell signaling. Compelling evidence has demonstrated that alterations in lipid rafts are associated with neurodegenerative diseases such Alzheimer's disease, but at present, whether alterations in lipid raft microdomains occurs in other types of dementia such Dementia with Lewy Bodies (DLB) remains unknown. Our analyses reveal that lipid rafts from DLB exhibit aberrant lipid profiles including low levels of n3 long chain polyunsaturated fatty acids (mainly docosahexaenoic acid), plasmalogens and cholesterol, and reduced unsaturation and peroxidability indexes. As a consequence, lipid raft resident proteins holding principal factors of the βamyloidogenic pathway, including β-amyloid precursor protein, presenilin 1, βsecretase and PrP, are redistributed between lipid rafts and non-raft domains in DLB frontal cortex. Meta-analysis discloses certain similarities in the altered composition of lipid rafts between DLB and Parkinson's disease which are in line with the spectrum of Lewy Body Diseases. In addition, redistribution of proteins linked to the β-amyloidogenic pathway in DLB can facilitate generation of β-amyloid, thus providing mechanistic clues to the intriguing convergence of Alzheimer's disease pathology, particularly β-amyloid deposition, in DLB

Lipid raft aging in the human frontal cortex during nonpathological aging: gender influences and potential implications in Alzehimer's disease

Lipid rafts are highly dynamic membrane domains featured by distinctive biochemical composition and physicochemical properties compared with the surrounding plasma membrane. These microstructures are associated not only with cellular signaling and communication in normal nerve cells but also with pathological processing of amyloid precursor protein in Alzheimer's disease. Using lipid rafts isolated from human frontal cortex in nondemented subjects aging 24 to 85 years, we demonstrate here that lipid structure of lipid rafts undergo significant alterations of specific lipid classes and phospholipid-bound fatty acids as brain cortex correlating with aging. Main changes affect levels of plasmalogens, polyunsaturated fatty acids (especially docosahexaenoic acid and arachidonic acid), total polar lipids (mainly phosphatidylinositol, sphingomyelin, sulfatides, and cerebrosides), and total neutral lipids (particularly cholesterol and sterol esters). Besides, relevant relationships between main fatty acids and/or lipid classes were altered in an age-related manner. This 'lipid raft aging' exhibits clear gender differences and appear to be more pronounced in women than in men, especially in older (postmenopausal) women. The outcomes led us to conclude that human cortical lipid rafts are modified by aging in a gender-dependent fashion. Given the central role of bilayer lipid matrix in lipid rafts functionality and neuronal signaling, we hypothesize that these findings might underlie the higher prevalence of cognitive decline evolving toward Alzheimer's disease in postmenopausal women

Evidence for premature "Lipid raft aging" in APP/PS1 double transgenic mice, a familial model of Alzheimer's disease

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Severe alterations in lipid composition of frontal cortex lipid rafts from parkinson's disease and incidental parkinson's

Lipid rafts are cholesterol- and sphingomyelin-enriched microdomains that provide a highly saturated and viscous physicochemical microenvironment to promote protein-lipid and protein-protein interactions. We purified lipid rafts from human frontal cortex from normal, early motor stages of Parkinson's disease (PD) and incidental Parkinson's disease (iPD) subjects and analyzed their lipid composition. We observed that lipid rafts from PD and iPD cortices exhibit dramatic reductions in their contents of n-3 and n-6 long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (22:6-n3) and arachidonic acid (20:4n-6). Also, saturated fatty acids (16:0 and 18:0) were significantly higher than in control brains. Paralleling these findings, unsaturation and peroxidability indices were considerably reduced in PD and iPD lipid rafts. Lipid classes were also affected in PD and iPD lipid rafts. Thus, phosphatidylserine and phosphatidylinositol were increased in PD and iPD, whereas cerebrosides and sulfatides and plasmalogen levels were considerably diminished. Our data pinpoint a dramatic increase in lipid raft order due to the aberrant biochemical structure in PD and iPD and indicate that these abnormalities of lipid rafts in the frontal cortex occur at early stages of PD pathology. The findings correlate with abnormal lipid raft signaling and cognitive decline observed during the development of these neurodegenerative disorders

Severe alterations in lipid composition of frontal cortex lipid rafts from parkinson's disease and incidental parkinson's

Lipid rafts are cholesterol- and sphingomyelin-enriched microdomains that provide a highly saturated and viscous physicochemical microenvironment to promote protein-lipid and protein-protein interactions. We purified lipid rafts from human frontal cortex from normal, early motor stages of Parkinson's disease (PD) and incidental Parkinson's disease (iPD) subjects and analyzed their lipid composition. We observed that lipid rafts from PD and iPD cortices exhibit dramatic reductions in their contents of n-3 and n-6 long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (22:6-n3) and arachidonic acid (20:4n-6). Also, saturated fatty acids (16:0 and 18:0) were significantly higher than in control brains. Paralleling these findings, unsaturation and peroxidability indices were considerably reduced in PD and iPD lipid rafts. Lipid classes were also affected in PD and iPD lipid rafts. Thus, phosphatidylserine and phosphatidylinositol were increased in PD and iPD, whereas cerebrosides and sulfatides and plasmalogen levels were considerably diminished. Our data pinpoint a dramatic increase in lipid raft order due to the aberrant biochemical structure in PD and iPD and indicate that these abnormalities of lipid rafts in the frontal cortex occur at early stages of PD pathology. The findings correlate with abnormal lipid raft signaling and cognitive decline observed during the development of these neurodegenerative disorders

Anomalies occurring in lipid profiles and protein distribution in frontal cortex lipid rafts in dementia with Lewy bodies disclose neurochemical traits partially shared by Alzheimer's and Parkinson's diseases

Lipid rafts are highly dynamic membrane microdomains intimately associated with cell signaling. Compelling evidence has demonstrated that alterations in lipid rafts are associated with neurodegenerative diseases such Alzheimer's disease, but at present, whether alterations in lipid raft microdomains occurs in other types of dementia such Dementia with Lewy Bodies (DLB) remains unknown. Our analyses reveal that lipid rafts from DLB exhibit aberrant lipid profiles including low levels of n3 long chain polyunsaturated fatty acids (mainly docosahexaenoic acid), plasmalogens and cholesterol, and reduced unsaturation and peroxidability indexes. As a consequence, lipid raft resident proteins holding principal factors of the βamyloidogenic pathway, including β-amyloid precursor protein, presenilin 1, βsecretase and PrP, are redistributed between lipid rafts and non-raft domains in DLB frontal cortex. Meta-analysis discloses certain similarities in the altered composition of lipid rafts between DLB and Parkinson's disease which are in line with the spectrum of Lewy Body Diseases. In addition, redistribution of proteins linked to the β-amyloidogenic pathway in DLB can facilitate generation of β-amyloid, thus providing mechanistic clues to the intriguing convergence of Alzheimer's disease pathology, particularly β-amyloid deposition, in DLB

Anomalies occurring in lipid profiles and protein distribution in frontal cortex lipid rafts in dementia with Lewy bodies disclose neurochemical traits partially shared by Alzheimer's and Parkinson's diseases

Lipid rafts are highly dynamic membrane microdomains intimately associated with cell signaling. Compelling evidence has demonstrated that alterations in lipid rafts are associated with neurodegenerative diseases such Alzheimer's disease, but at present, whether alterations in lipid raft microdomains occurs in other types of dementia such Dementia with Lewy Bodies (DLB) remains unknown. Our analyses reveal that lipid rafts from DLB exhibit aberrant lipid profiles including low levels of n3 long chain polyunsaturated fatty acids (mainly docosahexaenoic acid), plasmalogens and cholesterol, and reduced unsaturation and peroxidability indexes. As a consequence, lipid raft resident proteins holding principal factors of the βamyloidogenic pathway, including β-amyloid precursor protein, presenilin 1, βsecretase and PrP, are redistributed between lipid rafts and non-raft domains in DLB frontal cortex. Meta-analysis discloses certain similarities in the altered composition of lipid rafts between DLB and Parkinson's disease which are in line with the spectrum of Lewy Body Diseases. In addition, redistribution of proteins linked to the β-amyloidogenic pathway in DLB can facilitate generation of β-amyloid, thus providing mechanistic clues to the intriguing convergence of Alzheimer's disease pathology, particularly β-amyloid deposition, in DLB