Alzheimer Disease: Farooqui T

Farooqui AA, Ong WY, Horrocks LA, Chen P, Farooqui T. · Department of Molecular and Cellular Biochemistry, The Ohio State University, 1645 Neil Avenue, Columbus, OH 43210, USA. · Brain Res Rev. · Pubmed #17959252 No free full text.

Abstract: Neural membranes are composed of glycerophospholipids, sphingolipids, cholesterol and proteins. The distribution of these lipids within the neural membrane is not random but organized. Neural membranes contain lipid rafts or microdomains that are enriched in sphingolipids and cholesterol. These rafts act as platforms for the generation of glycerophospholipid-, sphingolipid-, and cholesterol-derived second messengers, lipid mediators that are necessary for normal cellular function. Glycerophospholipid-derived lipid mediators include eicosanoids, docosanoids, lipoxins, and platelet-activating factor. Sphingolipid-derived lipid mediators include ceramides, ceramide 1-phosphates, and sphingosine 1-phosphate. Cholesterol-derived lipid mediators include 24-hydroxycholesterol, 25-hydroxycholesterol, and 7-ketocholesterol. Abnormal signal transduction processes and enhanced production of lipid mediators cause oxidative stress and inflammation. These processes are closely associated with the pathogenesis of acute neural trauma (stroke, spinal cord injury, and head injury) and neurodegenerative diseases such as Alzheimer disease. Statins, the HMG-CoA reductase inhibitors, are effective lipid lowering agents that significantly reduce risk for cardiovascular and cerebrovascular diseases. Beneficial effects of statins in neurological diseases are due to their anti-excitotoxic, antioxidant, and anti-inflammatory properties. Fish oil omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have similar anti-excitotoxic, antioxidant and anti-inflammatory effects in brain tissue. Thus the lipid mediators, resolvins, protectins, and neuroprotectins, derived from eicosapentaenoic acid and docosahexaenoic acid retard neuroinflammation, oxidative stress, and apoptotic cell death in brain tissue. Like statins, ingredients of fish oil inhibit generation of beta-amyloid and provide protection from oxidative stress and inflammatory processes. Collective evidence suggests that antioxidant, anti-inflammatory, and anti-apoptotic properties of statins and fish oil contribute to the clinical efficacy of treating neurological disorders with statins and fish oil. We speculate that there is an overlap between neurochemical events associated with neural cell injury in stroke and neurodegenerative diseases. This commentary compares the neurochemical effects of statins with those of fish oil.

Farooqui T. · Department of Entomology, The Ohio State University, Columbus, Ohio 43210, USA. · Neuroscientist. · Pubmed #17644763 No free full text.

Abstract: Biogenic amines, such as norepinephrine (in vertebrates) and octopamine (in invertebrates), have structural and functional similarities. These amines play crucial roles in animal behavior by modifying the synaptic output of relevant neurons. Increased levels of norepinephrine in the olfactory bulb preferentially increase mitral cell excitatory responses to olfactory nerve inputs, suggesting its critical role in modulating olfactory function including memory formation and/or recall of specific olfactory memories. Increased levels of octopamine in the antennal lobe play an important role in a reinforcement pathway involved in olfactory learning and memory in honeybees. Similar to adrenergic receptors in the human brain, activation of octopaminergic receptors in the honeybee brain induces specific second messenger pathways that change protein phosphorylation and/or gene expression, altering the activity and/or abundance of proteins responsible for neuronal signaling leading to changes in olfactory behavior. The author's studies in honeybees Apis mellifera indicate that oxidative stress plays a major role in olfactory dysfunction. A similar mechanism has been proposed for olfactory abnormalities in patients of Alzheimer disease and Parkinson disease. Due to similarities in cellular and molecular processes, which govern neuronal plasticity in humans and honeybees, the author proposes that the honeybee can be used as a potential and relatively simple model system for understanding human olfactory dysfunction during aging and in neurodegenerative diseases.

Farooqui AA, Horrocks LA, Farooqui T. · Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210, USA. · J Neurosci Res. · Pubmed #17393491 No free full text.

Abstract: The neural membranes contain phospholipids, sphingolipids, cholesterol, and proteins. Glycerophospholipids and sphingolipids are precursors for lipid mediators involved in signal transduction processes. Degradation of glycerophospholipids by phospholipase A(2) (PLA(2)) generates arachidonic acid (AA) and docosahexaenoic acids (DHA). Arachidonic acid is metabolized to eicosanoids and DHA is metabolized to docosanoids. The catabolism of glycosphingolipids generates ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. These metabolites modulate PLA(2) activity. Arachidonic acid, a product derived from glycerophospholipid catabolism by PLA(2), modulates sphingomyelinase (SMase), the enzyme that generates ceramide and phosphocholine. Furthermore, sphingosine 1-phosphate modulates cyclooxygenase, an enzyme responsible for eicosanoid production in brain. This suggests that an interplay and cross talk occurs between lipid mediators of glycerophospholipid and glycosphingolipid metabolism in brain tissue. This interplay between metabolites of glycerophospholipid and sphingolipid metabolism may play an important role in initiation and maintenance of oxidative stress associated with neurologic disorders as well as in neural cell proliferation, differentiation, and apoptosis. Recent studies indicate that PLA(2) and SMase inhibitors can be used as neuroprotective and anti-apoptotic agents. Development of novel inhibitors of PLA(2) and SMase may be useful for the treatment of oxidative stress, and apoptosis associated with neurologic disorders such as stroke, Alzheimer disease, Parkinson disease, and head and spinal cord injuries.