Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Abstract

Oxidative stress, a hallmark of Alzheimer disease (AD), has been shown to induce lipid peroxidation and apoptosis disrupting cellular homeostasis. Normally, the aminophospholipid phosphatidylserine (PtdSer) is asymmetrically distributed on the cytosolic leaflet of the lipid bilayer. Under oxidative stress conditions, asymmetry is altered, characterized by the appearance of PtdSer on the outer leaflet, to initiate the first stages of an apoptotic process. PtdSer asymmetry is actively maintained by the ATP-dependent translocase flippase, whose function is inhibited if covalently bound by lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein, within the membrane bilayer in which they are produced. Additionally, pro-apoptotic proteins Bax and caspase-3 have been implemented in the oxidative modification of PtdSer resulting in subsequent asymmetric collapse, while antiapoptotic protein Bcl-2 has been found to prevent this process.The current investigation focused on detection of PtdSer on the outer leaflet of the bilayer in synaptosomes from brain of subjects with AD and amnestic mild cognitive impairment (MCI), as well as expression levels of apoptosis-related proteins Bcl-2, Bax, and caspase-3. Fluorescence and Western blot analysis suggest PtdSer exposure on the outer leaflet is significantly increased in brain from subjects with MCI and AD contributing to early apoptotic elevation of pro-and anti-apoptotic proteins and finally neuronal loss. MCI is considered a possible transition point between normal cognitive aging and probable AD. Brain from subjects with MCI is reported to have increased levels of tissue oxidation; therefore, the results of this study could mark the progression of patients with MCI into AD. This study contributes to a model of apoptosis-specific oxidation of phospholipids consistent with the notion that PtdSer exposure is required for apoptotic-cell death.

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…Loss of function and changes in conformation of PEBP conceivably could lead to loss of phospholipid asymmetry, a signal for neuronal apoptosis, which further supports the role of PEBP as a parapoptosis inhibitor (359). Loss of PEBP may impact lipid asymmetry, as loss of activity is observed in AD and MCI and mouse models of familial AD (23,24,166) and can potentially disrupt cellular homeostasis. PEBP levels are decreased in AD, which promotes amyloid beta accumulation in the Tg2576 transgenic mouse model of AD (166).…”

“…A Schiff base is formed by reacting 3AT with pyridine-2-carboxyaldehyde, resulting in a metal-chelating motif that can be captured using an NTA column with a magnetic separator to sort non-nitrated and 3-NT-peptides (112). An enrichment procedure based on the solvophobic properties of fluorinated carbonated groups and their preference to be localized in a fluorine-rich environment has been manipulated for the identification of 3-NT-Angiotensin II and 3-NT-bovine serum albumin spiked into HeLa cell lysate digests (23). Fluorinated carbon-tagged peptides are captured by solid phase extraction with fluorinated carbon-linked silica beads, a chemistry based on fluorine-fluorine interactions.…”

“…Fluorinated carbon-tagged peptides are captured by solid phase extraction with fluorinated carbon-linked silica beads, a chemistry based on fluorine-fluorine interactions. Using this new approach, 28 nitrated peptides from human hepatoma cell line, Huh7, have been identified (23).…”

“…Ab aggregation is observed primarily in SPs; therefore, plasminogen can influence Ab degradation and enolase regulation. Protein modification of Eno1 may disrupt neuronal energy metabolism and ion homeostasis, thereby impairing ion-motive ATPases, signal transduction, membrane asymmetry (23), and glucose and glutamate transporters (238). Such metabolic and oxidative compromise, known to exist in AD (219,238,269), may thereby render neurons susceptible to excitotoxicity and apoptosis.…”

Soy Lecithin-Derived Phosphatidylserine Plus Phosphatidic Acid: Effects on Brain Functions in Elderly Patients with Alzheimer's Disease and Dementia

“…Oxidative stress on neuronal membranes also has a detrimental effect on synaptosomal PS asymmetry, which is normally maintained by the ATP-requiring enzyme flippase [38]. Accordingly, the appearance of PS in the outer membrane leaflet is a signal of synaptosomal apoptosis, which was also observed in brain post-mortem autopsies of patients with mild cognitive impairment and AD [39]. Next to the PS distribution, also its overall level is likely to have an impact: In PC12 cells with induced apoptosis, a reduction in the level of PS was detectable before the detection of apoptosis [40].…”