Cell Surface Binding and Internalization of Aβ Modulated by Degree of Aggregation

The amyloid peptides, Aβ40 and Aβ42, are generated through endoproteolytic cleavage of the amyloid precursor protein. Here we have developed a model to investigate the interaction of living cells with various forms of aggregated Aβ40/42. After incubation at endosomal pH 6, we observed a variety of Aβ conformations after 3 (Aβ3), 24 (Aβ24), and 90 hours (Aβ90). Both Aβ4224 and Aβ4024 were observed to rapidly bind and internalize into differentiated PC12 cells, leading to accumulation in the lysosome. In contrast, Aβ40/4290 were both found to only weakly associate with cells, but were observed as the most aggregated using dynamic light scattering and thioflavin-T. Internalization of Aβ40/4224 was inhibited with treatment of monodansylcadaverine, an endocytosis inhibitor. These studies indicate that the ability of Aβ40/42 to bind and internalize into living cells increases with degree of aggregation until it reaches a maximum beyond which its ability to interact with cells diminishes drastically

A Model for Classical Space-time Co-ordinates

Field equations with general covariance are interpreted as equations for a target space describing physical space time co-ordinates, in terms of an underlying base space with conformal invariance. These equations admit an infinite number of inequivalent Lagrangian descriptions. A model for reparametrisation invariant membranes is obtained by reversing the roles of base and target space variables in these considerations.Comment: 9 pages, Latex. This was the basis of a talk given at the Argonne National Laboratory 1996 Summer Institute : Topics on Non-Abelian Duality June 27-July 1

Requirement of aggregation propensity of Alzheimer amyloid peptides for neuronal cell surface binding

<p>Abstract</p> <p>Background</p> <p>Aggregation of the amyloid peptides, Aβ40 and Aβ42, is known to be involved in the pathology of Alzheimer's disease (AD). Here we investigate the relationship between peptide aggregation and cell surface binding of three forms of Aβ (Aβ40, Aβ42, and an Aβ mutant).</p> <p>Results</p> <p>Using confocal microscopy and flow cytometry with fluorescently labelled Aβ, we demonstrate a correlation between the aggregation propensity of the Alzheimer amyloid peptides and their neuronal cell surface association. We find that the highly aggregation prone Aβ42 associates with the surface of neuronal cells within one hour, while the less aggregation prone Aβ40 associates over 24 hours. We show that a double mutation in Aβ42 that reduces its aggregation propensity also reduces its association with the cell surface. Furthermore, we find that a cell line that is resistant to Aβ cytotoxicity, the non-neuronal human lymphoma cell line U937, does not bind either Aβ40 or Aβ42.</p> <p>Conclusion</p> <p>Taken together, our findings reveal that amyloid peptide aggregation propensity is an essential determinant of neuronal cell surface association. We anticipate that our approach, involving Aβ imaging in live cells, will be highly useful for evaluating the efficacy of therapeutic drugs that prevent toxic Aβ association with neuronal cells.</p

Friendsourcing Peer Support for Alzheimer’s Caregivers Using Facebook Social Media

This research piloted an e-health intervention that used social media to friendsource peer support for Alzheimer’s disease (AD) caregivers. Friendsourcing is a variant of crowdsourcing. Crowdsourcing recruits online participants who share a characteristic that makes their volunteerism meaningful when they join to achieve an outcome. Friendsourcing recruits online participants who share membership in a social network that makes their volunteerism meaningful when they join to achieve an outcome. This article introduces our friendsourcing intervention research and examines the effects on the psychological well-being of AD caregivers. After a 6-week intervention, caregivers were found to have significantly decreased burden (Z = −2.01, p < .05) and perceived stress (Z = −2.95, p < .01). Emotional and informational support scores were significantly increased (Z = −2.32, p < .05). Qualitative data analysis of the intervention identified positive effects in new caregiving knowledge acquisition and application and reduced stress in the acceptance of the caregiving role. Joining social networks in support groups through friendsourcing was feasible for AD caregivers who were familiar with social media, and can provide another means of guiding the development of their personal support networks

Solving the 3D Ising Model with the Conformal Bootstrap

We study the constraints of crossing symmetry and unitarity in general 3D Conformal Field Theories. In doing so we derive new results for conformal blocks appearing in four-point functions of scalars and present an efficient method for their computation in arbitrary space-time dimension. Comparing the resulting bounds on operator dimensions and OPE coefficients in 3D to known results, we find that the 3D Ising model lies at a corner point on the boundary of the allowed parameter space. We also derive general upper bounds on the dimensions of higher spin operators, relevant in the context of theories with weakly broken higher spin symmetries.Comment: 32 pages, 11 figures; v2: refs added, small changes in Section 5.3, Fig. 7 replaced; v3: ref added, fits redone in Section 5.

A category-specific advantage for numbers in verbal short-term memory: Evidence from semantic dementia

This study explored possible reasons for the striking difference between digit span and word span in patients with semantic dementia. Immediate serial recall (ISR) of number and non-number words was examined in four patients. For every case, the recall of single-digit numbers was normal whereas the recall of non-number words was impaired relative to controls. This difference extended to multi-digit numbers, and remained even when frequency, imageability, word length, set size and size of semantic category were matched for the numbers and words. The advantage for number words also applied to the patients' reading performance. Previous studies have suggested that semantic memory plays a critical role in verbal short-term memory (STM) and reading: patients with semantic dementia show superior recall and reading of words that are still relatively well known compared to previously known but now semantically degraded words. Additional assessments suggested that this semantic locus was the basis of the patients' category-specific advantage for numbers. Comprehension was considerably better for number than non-number words. Number knowledge may be relatively preserved in semantic dementia because the cortical atrophy underlying the condition typically spares the areas of the parietal lobes thought to be crucial in numerical cognition but involves the inferolateral temporal-lobes known to support general conceptual knowledge. © 2003 Elsevier Ltd. All rights reserved

Evidence that BDNF regulates heart rate by a mechanism involving increased brainstem parasympathetic neuron excitability

Autonomic control of heart rate is mediated by cardioinhibitory parasympathetic cholinergic neurons located in the brainstem and stimulatory sympathetic noradrenergic neurons. During embryonic development the survival and cholinergic phenotype of brainstem autonomic neurons is promoted by brain-derived neurotrophic factor (BDNF). We now provide evidence that BDNF regulates heart rate by a mechanism involving increased brainstem cardioinhibitory parasympathetic activity. Mice with a BDNF haploinsufficiency exhibit elevated resting heart rate, and infusion of BDNF intracerebroventricularly reduces heart rate in both wild-type and BDNF+/− mice. The atropine-induced elevation of heart rate is diminished in BDNF+/− mice and is restored by BDNF infusion, whereas the atenolol-induced decrease in heart rate is unaffected by BDNF levels, suggesting that BDNF signaling enhances parasympathetic tone which is diminished with BDNF haploinsufficiency. Whole-cell recordings from pre-motor cholinergic cardioinhibitory vagal neurons in the nucleus ambiguus indicate that BDNF haploinsufficiency reduces cardioinhibitory vagal neuron activity by increased inhibitory GABAergic and diminished excitatory glutamatergic neurotransmission to these neurons. Our findings reveal a previously unknown role for BDNF in the control of heart rate by a mechanism involving increased activation of brainstem cholinergic parasympathetic neurons Mice with reduced BDNF levels exhibit elevated heart rate, and infusion of BDNF into the brain normalizes heart rate by a mechanism involving increased brainstem cardioinhibitory parasympathetic activity. Recordings from pre-motor cholinergic cardioinhibitory vagal neurons (CVNs) in the nucleus ambiguus indicate that BDNF increases CVN activity by increasing excitatory glutamatergic and decreasing inhibitory GABAergic neurotransmission to these neurons. Perhaps factors that increase parasympathetic tone (e.g., exercise) reduce resting heart rate, in part, by a BDNF-mediated mechanism