Abstract
Alzheimer’s disease (AD) is characterized by extracellular accumulation of amyloid-β peptide (Aβ), generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. Aβ generation is inhibited when the initial ectodomain shedding is caused by α-secretase, cleaving APP within the Aβ domain. Therefore, an increase in α-secretase activity is an attractive therapeutic target for AD treatment. APP and the APP-cleaving secretases are all transmembrane proteins, thus local membrane lipid composition is proposed to influence APP processing. Although several studies have focused on γ-secretase, the effect of the membrane lipid microenvironment on α-secretase is poorly understood. In the present study, we systematically investigated the effect of fatty acid (FA) acyl chain length (10:0, 12:0, 14:0, 16:0, 18:0, 20:0, 22:0, 24:0), membrane polar lipid headgroup (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine), saturation grade and the FA double-bond position on α-secretase activity. We found that α-secretase activity is significantly elevated in the presence of FAs with short chain length and in the presence of polyunsaturated FAs, whereas variations in the phospholipid headgroups, as well as the double-bond position, have little or no effect on α-secretase activity. Overall, our study shows that local lipid membrane composition can influence α-secretase activity and might have beneficial effects for AD.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia among neurodegenerative diseases in the industrialized nations and is characterized by a progressive memory loss and cognitive failure
We prepared purified membranes of the human neuroblastoma cell line SH-SY5Y containing the membrane protein secretases involved in amyloid precursor protein (APP) processing, incubated them with the PC phospholipids mentioned above, and measured α-secretase activity directly by in vitro processing of a fluorogenic α-secretase substrate
As PC18:1 ∆9-cis (PC18):0 revealed no effect on α-secretase activity compared to purified SH-SY5Y membranes incubated with the solvent ethanol (Figure S1), and PC18:0 is one of the major PC species in the membrane (Table S5), PC18:0 represents the control fatty acid (FA) throughout our study addressing FA carbon chain length
Summary
Alzheimer’s disease (AD) is the most common cause of dementia among neurodegenerative diseases in the industrialized nations and is characterized by a progressive memory loss and cognitive failure. As APP itself and the secretases involved in APP cleavage are all integral membrane proteins, lipid composition of cellular membranes is discussed as influencing the proteolytic processing of APP [18,19,20,21], either by directly affecting secretase activities, or by modulating the dynamics and accessibility of APP to the cleaving proteases [22,23,24]. The effect of different phospholipids on non-amyloidogenic APP processing is poorly investigated. As phospholipids determine the local microenvironment of transmembrane proteins and influence e.g., membrane fluidity, which is important for lateral movement of transmembrane proteins within the phospholipid bilayer, we systematically investigated the effect of specific phospholipids on α-secretase activity in different in vitro systems and in living cells
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