European Journal of Pharmacology (v.545, #1)

Preface by M. Di Luca (1).

Excitotoxicity is thought to be a major mechanism in many human disease states such as ischemia, trauma, epilepsy and chronic neurodegenerative disorders. Briefly, synaptic overactivity leads to the excessive release of glutamate that activates postsynaptic cell membrane receptors, which upon activation open their associated ion channel pore to produce ion influx. To date, although molecular basis of glutamate toxicity remain uncertain, there is general agreement that N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors plays a key role in mediating at least some aspects of glutamate neurotoxicity. On this view, research has focused in the discovery of new compounds able to either reduce glutamate release or activation of postsynaptic NMDA receptors. Although NMDA receptor antagonists prevent excitotoxicity in cellular and animal models, these drugs have limited usefulness clinically. Side effects such as psychosis, nausea, vomiting, memory impairment, and neuronal cell death accompany complete NMDA receptor blockade, dramatizing the crucial role of the NMDA receptor in normal neuronal processes. Recently, however, well-tolerated compounds such as memantine has been shown to be able to block excitotoxic cell death in a clinically tolerated manner. Understanding the biochemical properties of the multitude of NMDA receptor subtypes offers the possibility of developing more effective and clinically useful drugs. The increasing knowledge of the structure and function of this postsynaptic NMDA complex may improve the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for brain disorders.
Keywords: NMDA receptor; Excitotoxicity; Postsynaptic density;

Altered synaptic function in Alzheimer's disease by Karen F.S. Bell; A. Claudio Cuello (11-21).
Alzheimer's disease is the leading cause of dementia in the elderly, presenting itself clinically by progressive loss of memory and learning. Since synaptic density correlates more closely with cognitive impairment than any other pathological lesion observable in the disease pathology, an increased understanding of the mechanisms behind synaptic disconnection is of vital importance. Our lab investigated the neurotransmitter-specific status of distinct cortical presynaptic bouton populations in various transgenic mouse models of the Alzheimer's-like amyloid pathology in order to assess their involvement throughout the progression of the pathology. These studies have revealed that the amyloid pathology appears to progress in a neurotransmitter-specific manner where the cholinergic terminals appear most vulnerable, followed by the glutamatergic terminals and finally by the somewhat more resilient GABAergic terminals. This review will discuss additional studies which also provide evidence of a neurotransmitter-specific pathology as well as comment on the potential explanations for the observed vulnerabilities, touching upon metabolic demand, trophic support and receptor mediated activation.
Keywords: Alzheimer's disease; Presynaptic boutons; Amyloid beta protein; Dystrophic neurites; Glutamate; GABA; Acetylcholine;

The nuclear transcription factors κB (NF-κB) function as key regulators of physiological processes in the central nervous system. Aberrant regulation of NF-κB can underlie neurological disorders associated with neurodegeneration. A large number of studies have reported a dual role of NF-κB in regulating neuron survival in pathological conditions. A recent progress in understanding the mechanisms responsible for opposite effects elicited by NF-κB in brain dysfunctions arises from the identification of diverse NF-κB complexes specifically involved in the mechanism of neuronal cell death or cell survival. We here discuss the latest findings and consider the therapeutic potential of targeting distinct NF-κB complexes for the treatment of neurodegenerative disorders and memory dysfunctions.
Keywords: Nuclear factor-kappaB; Neurodegeneration; Cell death; Amyloid beta; c-Rel; p65;

Pathogenic mechanisms in Alzheimer's disease by Lucia Pastorino; Kun Ping Lu (29-38).
Alzheimer's disease is a progressive neurodegenerative disorder associated with aging and characterized by neurofibrillary tangles and amyloid plaques that deposit in the brain, triggering the neurodegenerative phenomena and leading to neuronal death. Amyloid plaques are primarily composed of β-amyloid peptides, which derive from the Amyloid Precursor Protein (APP) upon the consequential action of β- and γ-secretase. This review discusses recent literature on β- and γ-secretase, and on those cellular factors, like cholesterol and phosphorylation of APP, that are involved in aging and may affect the function of both β- and γ-secretase.
Keywords: Amyloid precursor protein; β-Secretase; γ-Secretase; Amyloidogenic processing;

Oxidative stress in Alzheimer's disease brain: New insights from redox proteomics by D. Allan Butterfield; Marzia Perluigi; Rukhsana Sultana (39-50).
Alzheimer's disease, an age-related neurodegenerative disorder, is characterized clinically by a progressive loss of memory and cognitive functions. Neuropathologically, Alzheimer's disease is defined by the accumulation of extracellular amyloid protein deposited senile plaques and intracellular neurofibrillary tangles made of abnormal and hyperphosphorylated tau protein, regionalized neuronal death, and loss of synaptic connections within selective brain regions. Evidence has suggested a critical role for amyloid-β peptide metabolism and oxidative stress in Alzheimer's disease pathogenesis and progression. Among the other indices of oxidative stress in Alzheimer's disease brain are protein carbonyls and 3-nitrotyrosine, which are the markers of protein oxidation. Thus, in this review, we discuss the application of redox proteomics for the identification of oxidatively modified proteins in Alzheimer's disease brain and also discuss the functions associated with the identified oxidized proteins in relation to Alzheimer's disease pathology. The information obtained from proteomics may be helpful in understanding the molecular mechanisms involved in the development and progression of Alzheimer's disease as well as of other neurodegenerative disorders. Further, redox proteomics may provide potential targets for drug therapy in Alzheimer's disease.
Keywords: Redox proteomics; Alzheimer's disease; Oxidative stress; Protein oxidation; Hippocampus; Inferior parietal lobule;

Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. A large body of evidence indicates that oxidative stress is involved in the pathophysiology of these diseases. Oxidative stress can induce neuronal damages, modulate intracellular signaling, ultimately leading to neuronal death by apoptosis or necrosis. Thus antioxidants have been studied for their effectiveness in reducing these deleterious effects and neuronal death in many in vitro and in vivo studies. Increasing number of studies demonstrated the efficacy of polyphenolic antioxidants from fruits and vegetables to reduce or to block neuronal death occurring in the pathophysiology of these disorders. These studies revealed that other mechanisms than the antioxidant activities could be involved in the neuroprotective effect of these phenolic compounds. We will review some of these mechanisms and particular emphasis will be given to polyphenolic compounds from green tea, the Ginkgo biloba extract EGb 761, blueberries extracts, wine components and curcumin.
Keywords: Amyloid synthesis; Green tea; Curcumin; Blueberries; Resveratrol; Ginkgo biloba extract EGb 761;

Pathways of neurodegeneration and experimental models of basal ganglia disorders: Downstream effects of mitochondrial inhibition by Massimiliano Di Filippo; Barbara Picconi; Cinzia Costa; Vincenza Bagetta; Michela Tantucci; Lucilla Parnetti; Paolo Calabresi (65-72).
The basal ganglia circuit plays a key role in the regulation of voluntary movements as well as in behavioural control and cognitive functions. The main pathogenic role of mitochondrial dysfunctions is now accepted in the neurodegenerative process and the mitochondria have been successfully used as subcellular targets to obtain relevant experimental models of basal ganglia neurodegenerative disorders. Mitochondrial toxins act through an inhibition of the respiratory chain complexes. These toxins, by uncoupling cellular respiration, shift the cell into a state of oxidative stress and trigger several bidirectional links with the excitotoxic process. Moreover, the in vitro inhibition of the respiratory chain complexes alters the electrophysiological properties of the neurons. The downstream effects triggered by mitochondrial complexes inhibition provide a model integrating genetic and environmental pathogenic factors to explain the selective neuronal vulnerability.
Keywords: Basal ganglia; Parkinson's disease; Huntington's disease; Mitochondria;

Predicting Alzheimer dementia in mild cognitive impairment patients by Barbara Borroni; Monica Di Luca; Alessandro Padovani (73-80).
A correct clinical diagnosis in the early stage of Alzheimer disease is not only of importance given the current available treatment with acetylcholine esterase inhibitors, but would be the basis for disease-modifying therapy slowing down or arresting the degenerative process. Moreover, in the last years, several efforts have been made to determine if a patient with mild cognitive impairment has incipient Alzheimer disease, i.e. will progress to Alzheimer disease with dementia, or have a benign form of mild cognitive impairment. In this review, the recent published reports regarding progress in early and preclinical Alzheimer disease diagnosis are discussed and the role of peripheral and cerebrospinal fluid biomarkers highlighted. Approaches combining panels of different biomarkers show promise for discovering profiles that are characteristic of Alzheimer disease, even in the pre-symptomatic stage. More work is needed but available novel perspectives offered by recent introduced technologies shed some lights in identifying incipient Alzheimer disease in mild cognitive impairment subjects.
Keywords: Alzheimer disease; Mild cognitive impairment; Biomarker; Cerebrospinal fluid; Amyloid precursor protein; Platelet;