Lipid composition influences the release of Alzheimer's amyloid β‐peptide from membranes

Abstract

The behavior of the amyloid b-peptide (Ab) within a membrane environment is integral to its toxicity and the progression of Alzheimer's disease. Ganglioside GM1 has been shown to enhance the aggregation of Ab, but the underlying mechanism is unknown. Using atomistic molecular dynamics simulations, we explored the interactions between the 40-residue alloform of Ab (Ab 40 ) and several model membranes, including pure palmitoyloleoylphosphatidylcholine (POPC) and palmitoyloleoylphosphatidylserine (POPS), an equimolar mixture of POPC and palmitoyloleoylphosphatidylethanolamine (POPE), and lipid rafts, both with and without GM1, to understand the behavior of Ab 40 in various membrane microenvironments. Ab 40 remained inserted in POPC, POPS, POPC/POPE, and raft membranes, but in several instances exited the raft containing GM1. Ab 40 interacted with GM1 largely through hydrogen bonding, producing configurations containing b-strands with C-termini that, in some cases, exited the membrane and became exposed to solvent. These observations provide insight into the release of Ab from the membrane, a previously uncharacterized process of the Ab aggregation pathway.

Scaling and alpha-helix regulation of protein relaxation in a lipid bilayer

“…The anchoring of the Aß C-terminus to the cytofacial membrane interface has been seen in some simulations 24,26 but other conformations are common. Simulations addressing inserted Aß as the initial state show a wide range of behavior from anchoring to the extracellular membrane interface, 24,27,28 to ejection from the membrane.…”

“…Simulations addressing inserted Aß as the initial state show a wide range of behavior from anchoring to the extracellular membrane interface, 24,27,28 to ejection from the membrane. 26,31 However, few simulations 26 have addressed Aß interactions with membranes composed of CHOL and unsaturated lipids. Indeed, we see anchoring in only 3 of 8 cases for membranes that do not contain CHOL.…”

“…[24][25][26][27][28][29] Simulation of aggregation and release processes 26,30,31 are particularly relevant to the work presented here because they can compete with unfolding, penetration, and binding phenomena.…”

Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer's disease

“…These modifi cations in GP compositions may change cell membrane fl uidity, alter amyloid precursor protein processing, and infl uence the release of neurotoxic A ␤ 42 ( 49,50 ). An increase in PLA 2 activity combined with the higher LPC/PC in CSF is evidence of neuroinfl ammation in LOAD.…”

Alzheimer’s Disease Risk Genes and Lipid Regulators

“…Increased BACE1-mediated ␤APP cleavage also led to an increased release of ␤APP intracellular fragment AICD, which downregulated low-density lipoprotein-related protein 1 (LRP-1) transcription and decreased the amount of LRP1 receptor responsible for exogenous cholesterol capture at the plasma membrane [51]. It was shown that lowering cholesterol levels by statins and methyl-␤-cyclodextrine (M␤CD), respectively, reduced intracellular and extracellular levels of A␤ 40 and A␤ 42 in cultured neurons [49,52,53], suggesting that amyloidogenesis process is affected by cholesterol composition in lipid rafts [54].…”