Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.

Non-fibrillar soluble oligomeric forms of amyloid-ß peptide (oAß) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAß initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aß, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAß levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAß to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aß on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aß and tau pathology.

Age-related changes in dopamine transporters and accumulation of 3-nitrotyrosine in rhesus monkey midbrain dopamine neurons: relevance in selective neuronal vulnerability to degeneration.

Aging is the strongest risk factor for developing Parkinson's disease (PD). There is a preferential loss of dopamine (DA) neurons in the ventral tier of the substantia nigra (vtSN) compared to the dorsal tier and ventral tegmental area (VTA) in PD. Examining age-related and region-specific differences in DA neurons represents a means of identifying factors potentially involved in vulnerability or resistance to degeneration. Nitrative stress is among the factors potentially underlying DA neuron degeneration. We studied the relationship between 3-nitrotyrosine (3NT; a marker of nitrative damage) and DA transporters [DA transporter (DAT) and vesicular monoamine transporter-2 (VMAT)] during aging in DA subregions of rhesus monkeys. The percentage of DA neurons containing 3NT increased significantly only in the vtSN with advancing age, and the vtSN had a greater percentage of 3NT-positive neurons when compared to the VTA. The relationship between 3NT and DA transporters was determined by measuring fluorescence intensity of 3NT, DAT and VMAT staining. 3NT intensity increased with advancing age in the vtSN. Increased DAT, VMAT and DAT/VMAT ratios were associated with increased 3NT in individual DA neurons. These results suggest nitrative damage accumulates in midbrain DA neurons with advancing age, an effect exacerbated in the vulnerable vtSN. The capacity of a DA neuron to accumulate more cytosolic DA, as inferred from DA transporter expression, is related to accumulation of nitrative damage. These findings are consistent with a role for aging-related accrual of nitrative damage in the selective vulnerability of vtSN neurons to degeneration in PD.

Atrial and accessory pathway activation direction in patients with orthodromic supraventricular tachycardia: insights from vector mapping.

OBJECTIVES: The purpose of this study was to utilize vector mapping to investigate atrial and accessory pathway activation direction during orthodromic supraventricular tachycardia. BACKGROUND: Although advances have been made in the electrophysiologic evaluation and management of accessory pathways, our understanding of accessory pathway anatomy and physiology remains incomplete. Vector mapping has been validated as a method of studying local myocardial activation. METHODS: In 28 patients with a left-sided or posteroseptal accessory atrioventricular (AV) pathway referred for ablation, atrial and accessory AV pathway activation direction was determined during ventricular pacing or orthodromic supraventricular tachycardia, or both, by summing three orthogonally oriented bipolar electrograms recorded from the coronary sinus to create three-dimensional vector loops. Atrial and accessory AV pathway activation direction was determined in all patients from the maximal amplitude vectors of the vector loops. Because of beat to beat variability in the directions of the vector loops, data from 8 of 28 patients could not be analyzed. RESULTS: At 81 of 83 sites, atrial activation direction along the long axis of the coronary sinus corresponded with the direction suggested by activation time mapping. Activation direction along the anteroposterior and inferosuperior axes was variable, potentially due to variations in the level of the atrial insertion of the accessory AV pathway and in the depth or angling of pathway fibers in the AV fat pad. In eight patients, at least one recording was obtained at the site of an accessory AV pathway potential. Accessory AV pathway activation proceeded superiorly and to the right in seven of eight patients; in one patient with a posteroseptal pathway, accessory AV pathway activation proceeded superiorly and to the left. CONCLUSIONS: 1) Vector mapping is a useful technique for localizing accessory AV pathways; 2) left-sided accessory AV pathways angle from left to right as they traverse the AV groove; and 3) variable activation directions of the atrial myocardium adjacent to the coronary sinus suggest that accessory AV pathway insertion into the atrium differs from patient to patient.

Spatial and temporal linking of epicardial activation directions during ventricular fibrillation in dogs. Evidence for underlying organization.

BACKGROUND: It remains controversial as to whether electrical activation during ventricular fibrillation (VF) is organized. To detect the presence of organization in VF, the direction of epicardial activation (EA) at multiple sites was examined by using vector mapping. If VF is not a random process, EA direction at a given site should be related to adjacent sites and prior beats. METHODS AND RESULTS: Thirteen dogs with healing myocardial infarction (MI) and four dogs without MI had VF induced by programmed stimulation. Using a plaque electrode array with a 2.5-mm interelectrode distance, 91 vector loops were created for each "beat" of VF. Direction of maximum EA was determined at each site for the first 10 consecutive beats of VF and for 10 consecutive beats recorded 5 seconds after VF was established. Spatial and temporal linking of EA directions was evaluated by the ability of activation direction at a given site to be predicted by activation directions at eight adjacent sites for the index beat and at eight adjacent sites and the site of interest for the preceding beat using stepwise linear regression. The strength of the model as reflected by the correlation coefficient (r) indicated the degree of linking. We determined 1) changes in the degree of linking over time during a given episode of VF (using a paired-difference t test), 2) differences in the degree of linking between the anterior and posterolateral walls in animals with (n = 4) and without (n = 4) MI (using two-way ANOVA), and 3) the effect of repeated inductions (n = 10) on the degree of linking (using one-way ANOVA with repeated measures). During 57 episodes of VF, r for each model ranged from 0.64 to 0.88 during the transition to VF to 0.39-0.78 during established VF (p < 0.0001 for the difference). The presence of MI, the site of recording, and repeated inductions did not affect the degree of linking. For each episode, spatial linking was more prominent than temporal linking. CONCLUSIONS: Electrical activation during VF is organized. The degree of linking of EA directions during VF is not affected by the presence of MI, the site of recording, or repeated inductions of VF. During the first 5 seconds of VF, the degree of linking decreases.