Cerebral Arachidonate Cascade in Dementia: Alzheimers Disease and Vascular Dementia

Tatsurou      Yagami

Abstract

Phospholipase A2 (PLA2), cyclooxygenase (COX) and prostaglandin (PG) synthase are enzymes involved in arachidonate cascade. PLA2 liberates arachidonic acid (AA) from cell membrane lipids. COX oxidizes AA to PGG2 followed by an endoperoxidase reaction that converts PGG2 into PGH2. PGs are generated from astrocytes, microglial cells and neurons in the central nervous system, and are altered in the brain of demented patients. Dementia is principally diagnosed into Alzheimers disease (AD) and vascular dementia (VaD). In older patients, the brain lesions associated with each pathological process often occur together. Regional brain microvascular abnormalities appear before cognitive decline and neurodegeneration. The coexistence of AD and VaD pathology is often termed mixed dementia. AD and VaD brain lesions interact in important ways to decline cognition, suggesting common pathways of the two neurological diseases. Arachidonate cascade is one of the converged intracellular signal transductions between AD and VaD. PLA2 from mammalian sources are classified as secreted (sPLA2), Ca2+-dependent, cytosolic (cPLA2) and Ca2+-independent cytosolic PLA2 (iPLA2). PLA2 activity can be regulated by calcium, by phosphorylation, and by agonists binding to Gprotein- coupled receptors. cPLA2 is upregulalted in AD, but iPLA2 is downregulated. On the other hand, sPLA2 is increased in animal models for VaD. COX-2 is induced and PGD2 are elevated in both AD and VaD. This review presents evidences for central roles of PLA2s, COXs and PGs in the dementia.

Keywords: Alzheimer's disease, arachidonic acid, cyclooxygenase, mixed dementia, phospholipase A2, prostaglandin, vascular dementia, PGD2, 15δ- 12,14-PGJ2