Amyloid-β₄₂signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism

Abstract

Perturbation of lipid second messenger networks is associated with the impairment of synaptic function in Alzheimer disease. Underlying molecular mechanisms are unclear. Here, we used an unbiased lipidomic approach to profile alkylacylglycerophosphocholine second messengers in diseased tissue. We found that specific isoforms defined by a palmitic acid (16:0) at the sn-1 position, namely 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16:0 PAF) and 1-O-hexadecyl-sn-glycero-3-phosphocholine (C16:0 lyso-PAF), were elevated in the temporal cortex of Alzheimer disease patients, transgenic mice expressing human familial diseasemutant amyloid precursor protein, and human neurons directly exposed to amyloid-␤ 42 oligomers. Acute intraneuronal accumulation of C16:0 PAF but not C16:0 lyso-PAF initiated cyclindependent kinase 5-mediated hyperphosphorylation of tau on Alzheimer disease-specific epitopes. Chronic elevation caused a caspase 2 and 3/7-dependent cascade resulting in neuronal death. Pharmacological inhibition of C16:0 PAF signaling, or molecular strategies increasing hydrolysis of C16:0 PAF to C16:0 lyso-PAF, protected human neurons from amyloid-␤ 42 toxicity. Together, these data provide mechanistic insight into how disruptions in lipid metabolism can determine neuronal response to accumulating oligomeric amyloid-␤ 42.Alzheimer disease ͉ glycerophosphocholine ͉ lipidomics ͉ T he aberrant processing of the amyloid precursor protein to different assemblies of amyloid ␤ (A␤) peptides ranging from 37 to 42 amino acids is an early and necessary prerequisite for the development of Alzheimer disease (AD) (1). The ''amyloid cascade hypothesis'' defines generation of these smaller, toxic A␤ fragments, specifically soluble A␤ 42 oligomers, as the root cause of AD (1). The severity of AD progression, however, is highly correlated with the rate of abnormal tau processing (2). Underlying molecular mechanisms linking A␤ 42 biogenesis to the aggregation of normally soluble tau proteins into hyperphosphorylated oligomers remain elusive.A␤ 42 can activate cytosolic phospholipase A 2 (cPLA 2 ) (3, 4), a Group IVa PLA 2 that preferentially hydrolyzes arachidonic acid from the sn-2 position of 1-O-alkyl-2-arachidonoyl-and 1-O-acyl-2-arachidonoyl-glycerophospholipids (5). Inhibiting cPLA 2 activation completely attenuates A␤ 42 neurotoxicity; blocking the different metabolic arms of the arachidonic acid cascade confers only partial protection (3,4,6). Little is known about the fate of the glycerophospholipid backbone following the release of arachidonic acid by cPLA 2 , although accumulation of choline-containing lipids is associated with accelerated cognitive decline in AD (7,8). The alkyl-lyso-glycerophosphocholines and lysophosphatidylcholines (LPCs) are of particular interest (Fig. S1). These metabolites are biologically active in their own right and can be further modified by lysophosphatidylcholine acyltransferases (LPCATs). LPCAT activity also increases in AD (9), notably in the posterior-temporal entorhinal cortex, a r...

DHPC Strongly Affects the Structure and Oligomerization Propensity of Alzheimer's Aβ(1–40) Peptide

“…80 Moreover, there has been evidence that cell death occurring in the course of AD is associated with the activation of phospholipase A2 81 and that the temporal cortex of AD patients contains elevated levels of lysolipids. 82 As the lipid constellations that we analyzed here by using DHPC correspond, in their physicochemical properties, rather to soluble lipids or micelles than to intact lipid bilayers, our current data help to explain the properties of these soluble lipid systems and their potential impact in the context of protein misfolding and impairment of synaptic dysfunction in AD. The current work highlights the importance of lipid interactions with early aggregate species, providing compelling evidence for the ability of soluble lipids to alter the kinetics of amyloid fibril formation by Aβ.…”

β-Amyloid protein (Aβ) and human amylin regulation of apoptotic genes occurs through the amylin receptor

“…To determine the dose-dependent toxicity of Ab peptides and human amylin, HFNs were treated with different concentrations of (0.5-50 lM) of the peptides [24]. Final concentrations used in our experiments are based on these data and published reports using these peptides in cell toxicity assays [25][26][27].…”

Pannexin 2 Is Expressed by Postnatal Hippocampal Neural Progenitors and Modulates Neuronal Commitment

“…Immunoprecipitation was performed as described (38). After washing with RIPA buffer followed by PBS or 1 M hydroxylamine, pH 7.4, lipids were extracted using a modified Bligh and Dyer protocol (39).…”