Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Abstract

Soluble beta-amyloid (A␤) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that A␤ oligomers activate cytosolic phospholipase A 2 (cPLA 2 ), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA 2 gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of A␤ oligomers in wild type mice. We further demonstrated that the A␤ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA 2 Ϫ/Ϫ mice. Interestingly, expression of the A␤ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA 2 Ϫ/Ϫ mice, but the relationship with the resistance of these mice to the A␤ oligomer toxicity requires further investigation. These results therefore show that cPLA 2 plays a key role in the A␤ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.

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

“…Disturbance of membrane structures can also impede the transport and clearance of neurotoxic amyloid peptides ( 42,43 ). PLA 2 products have infl ammatory properties that can exacerbate the damage to brain tissues ( 44,45 ). Thus, the increase in PLA 2 activity that we measured in CSF may be expected to worsen LOAD pathophysiology by destroying cell membranes or by generating infl ammatory molecules.…”

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

“…This animal model has been used widely to test drug candidates for AD and has been consistently shown to induce cognitive impairment and neurodegeneration [21][22][23][24]. There were no cognition deficits using NORT (duration of sniffing novel object) apparent 1 week after the injection of Aβ (Fig.…”

Cytosolic phospholipase A2: physiological function and role in disease

“…The A ␤ peptides that are implicated in Alzheimer's neurodegeneration exert toxic effects in neurons, which are in part mediated by cPLA 2 ␣ ( 182, 183 ). Genetic ablation of cPLA 2 ␣ improves cognitive function in a mouse model of familial Alzheimer's disease, and protects from the toxic effects of intra-cerebroventricular injection of A ␤ oligomers ( 184,185 ). A recent study found that A ␤ peptides activate cPLA 2 ␣ in rat primary cortical neurons, resulting in increased expression of ␤ -amyloid precursor protein by an autocrine pathway involving PGE 2 production and increases in cAMP ( 186 ).…”