SAP97-mediated local trafficking is altered in Alzheimer disease patients' hippocampus

Synapse-asssociated protein-97 (SAP97) is responsible for the trafficking of both glutamate receptor subunits, GluR1 and NR2A, and \u3b1-secretase ADAM10 to the synaptic membrane. Here we evaluate the trafficking capability of SAP97 in Alzheimer disease (AD) patients' brain. We analyzed autoptic hippocampus and superior frontal gyrus, respectively as an affected and a less affected area, from 6 AD patients (Braak 4) and 6 healthy controls. In hippocampus, but not in superior frontal gyrus, of AD patients, ADAM10 and GluR1 synaptic membrane levels are altered while NR2A localization is not affected. Both immunoprecipitation and pull-down assays demonstrated that SAP97 failed to correctly couple to ADAM10 and GluR1, but not to NR2A. These findings not only indicate SAP97 as a point of convergence between amyloid cascade and synaptic failure in AD, but also allow a different interpretation of AD which can be now perceived as synaptic trafficking defect patholog

Perceived Surface Slant Is Systematically Biased in the Actively-Generated Optic Flow

Humans make systematic errors in the 3D interpretation of the optic flow in both passive and active vision. These systematic distortions can be predicted by a biologically-inspired model which disregards self-motion information resulting from head movements (Caudek, Fantoni, & Domini 2011). Here, we tested two predictions of this model: (1) A plane that is stationary in an earth-fixed reference frame will be perceived as changing its slant if the movement of the observer's head causes a variation of the optic flow; (2) a surface that rotates in an earth-fixed reference frame will be perceived to be stationary, if the surface rotation is appropriately yoked to the head movement so as to generate a variation of the surface slant but not of the optic flow. Both predictions were corroborated by two experiments in which observers judged the perceived slant of a random-dot planar surface during egomotion. We found qualitatively similar biases for monocular and binocular viewing of the simulated surfaces, although, in principle, the simultaneous presence of disparity and motion cues allows for a veridical recovery of surface slant

New targets for pharmacological intervention in the glutamatergic synapse

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

IN VIVO MODULATION OF STRIATAL PHOSPHOPROTEINS BY DOPAMINERGIC AGENTS

Protein phosphorylation in the brain represents a common target for several second messenger systems. A phosphoprotein (DARPP-32) specifically regulated by cAMP and dopamine has been detected in neurons bearing dopamine D-1 receptors, where it plays a key role in eliciting cAMP-mediated intracellular responses. The endogenous phosphorylation of this cytosolic protein is markedly affected after in vivo acute treatment with the selective D-1 agonist, SKF 38393. The amount of the DARPP-32 dephospho-form measured by a back-phosphorylation assay was decreased by about 30% in agonist-treated animals. This effect was completely counteracted by the concomitant administration of the selective D-1 antagonist, SCH 23390, but not by a selective D-2 antagonist. This first demonstration of in vivo modulation of the phosphorylation state of DARPP-32 could, as a biochemical approach, represent a useful tool to gain further insight into the cascade of biochemical events elicited by specific dopaminergic drugs

Predicting Alzheimer dementia in mild cognitive impairment patients. Are biomarkers useful?

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