CSF sTREM2: Marking the tipping point between preclinical AD and dementia?

Biomarkers for Alzheimer's disease (AD) have improved our understanding of the temporal sequence of biological events that lead to AD dementia (Jack et al, 2013). AD is characterized neuropathologically by amyloid plaques comprised of the amyloid‐β peptide and neurofibrillary tangles comprised of tau. Brain amyloid deposition, as evidenced by a decline in amyloid‐β peptide 42 (Aβ42) in the cerebrospinal fluid (CSF) or by binding of amyloid PET ligands, is thought to be a key initiating event in AD and begins many years prior to the onset of dementia. A rise in CSF tau and phosphorylated tau in the setting of Aβ deposition appears to reflect neurodegeneration and also begins years prior to the onset of dementia but after Aβ deposition has begun to accumulate. Individuals with “preclinical AD,” that is, normal cognition but abnormal AD biomarkers, have a much higher risk for developing AD dementia but may remain cognitively normal for years (Vos et al, 2013). While deposition of amyloid and formation of tau tangles are necessary for AD to occur, it is likely that additional events involving inflammation or other processes contribute to crossing the tipping point from preclinical AD to AD dementia. Current efforts are aimed at defining the biomarker(s) that best predict the transition from cognitive normality to abnormality. A biomarker that is closely associated with the onset of cognitive decline could help us to understand the biological events that connect amyloid deposition and tangle formation to cognitive decline and could have significant practical value in AD diagnosis and clinical trial design

Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-β accumulation and independently accelerates the development of tau abnormalities

Alzheimer\u27s disease (AD) is a neurodegenerative disorder characterized pathologically by progressive neuronal loss, extracellular plaques containing the amyloid-β (Aβ) peptides, and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Aβ is thought to act upstream of tau, affecting its phosphorylation and therefore aggregation state. One of the major risk factors for AD is traumatic brain injury (TBI). Acute intra-axonal Aβ and diffuse extracellular plaques occur in ∼30% of human subjects after severe TBI. Intra-axonal accumulations of tau but not tangle-like pathologies have also been found in these patients. Whether and how these acute accumulations contribute to subsequent AD development is not known, and the interaction between Aβ and tau in the setting of TBI has not been investigated. Here, we report that controlled cortical impact TBI in 3xTg-AD mice resulted in intra-axonal Aβ accumulations and increased phospho-tau immunoreactivity at 24 h and up to 7 d after TBI. Given these findings, we investigated the relationship between Aβ and tau pathologies after trauma in this model by systemic treatment of Compound E to inhibit γ-secretase activity, a proteolytic process required for Aβ production. Compound E treatment successfully blocked posttraumatic Aβ accumulation in these injured mice at both time points. However, tau pathology was not affected. Our data support a causal role for TBI in acceleration of AD-related pathologies and suggest that TBI may independently affect Aβ and tau abnormalities. Future studies will be required to assess the behavioral and long-term neurodegenerative consequences of these pathologies

The Bulge-Halo Connection in Galaxies: A Physical Interpretation of the Vcirc-sigma_0 Relation

We explore the dependence of the ratio of a galaxy's circular velocity, Vcirc, to its central velocity dispersion, sigma_0, on morphology, or equivalently total light concentration. Such a dependence is expected if light traces the mass. Over the full range of galaxy types, masses and brightnesses, and assuming that the gas velocity traces the circular velocity, we find that galaxies obey the relation log(Vcirc/sigma_0)= 0.63-0.11*C28 where C28=5log(r80/r20) and the radii are measured at 80 percent and 20 percent of the total light. Massive galaxies scatter about the Vcirc = sqrt(2)*sigma_0 line for isothermal stellar systems. Disk galaxies follow the simple relation Vcirc/sigma_0=2(1-B/T), where B/T is the bulge-to-total light ratio. For pure disks, C28~2.8, B/T -> 0, and Vcirc~=2*sigma_0. Self-consistent equilibrium galaxy models from Widrow & Dubinski (2005) constrained to match the size-luminosity and velocity-luminosity relations of disk galaxies fail to match the observed Vcirc/sigma_0 distribution. Furthermore, the matching of dynamical models for Vcirc(r)/sigma(r) with observations of dwarf and elliptical galaxies suffers from limited radial coverage and relatively large error bars; for dwarf systems, however, kinematical measurements at the galaxy center and optical edge suggest Vcirc(Rmax) > 2*sigma_0 (in contrast with past assumptions that Vcirc = sqrt(2)*sigma_0 for dwarfs.) The Vcirc-sigma_0-C28 relation has direct implications for galaxy formation and dynamical models, galaxy scaling relations, the mass function of galaxies, and the links between respective formation and evolution processes for a galaxy's central massive object, bulge, and dark matter halo.Comment: Accepted for publication in ApJL. Current version matches ApJL page requiremen

Changes in insulin and insulin signaling in Alzheimer\u27s disease: Cause or consequence?

Individuals with type 2 diabetes have an increased risk for developing Alzheimer’s disease (AD), although the causal relationship remains poorly understood. Alterations in insulin signaling (IS) are reported in the AD brain. Moreover, oligomers/fibrils of amyloid-β (Aβ) can lead to neuronal insulin resistance and intranasal insulin is being explored as a potential therapy for AD. Conversely, elevated insulin levels (ins) are found in AD patients and high insulin has been reported to increase Aβ levels and tau phosphorylation, which could exacerbate AD pathology. Herein, we explore whether changes in ins and IS are a cause or consequence of AD

Optical identification of the companion to PSR J1911-5958A, the pulsar binary in the outskirts of NGC 6752

We report on the identification of the optical counterpart of the binary millisecond pulsar PSR J1911-5958A, located in the outskirts of the globular cluster NGC 6752. At the position of the pulsar we find an object with V=22.08, B-V=0.38, U-B=-0.49. The object is blue with respect to the cluster main sequence by 0.8 magnitudes in B-V. We argue that the object is the white dwarf companion of the pulsar. Comparison with white dwarf cooling models shows that this magnitude and colors are consistent with a low-mass white dwarf at the distance of NGC 6752. If associated with NGC 6752, the white dwarf is relatively young, <2 Gyr, which sets constraints on the formation of the binary and its ejection from the core of the globular cluster.Comment: Accepted for publication in A&A Letters (September 1st, 2003

Altered sleep and EEG power in the P301S Tau transgenic mouse model

OBJECTIVE: Sleep disturbances are prevalent in human tauopathies yet despite the importance of sleep, little is known about its relationship with tau pathology. Here, we investigate this interaction by analyzing sleep and tau pathology throughout tauopathy disease progression in P301S human tau transgenic mice. METHODS: P301S and wild‐type mice were analyzed by electroencephalography (EEG)/electromyography at 3, 6, 9, and 11 months of age for sleep/wake time, EEG power, and homeostatic response. Cortical volume and tau pathology was also assessed by anti‐phospho‐tau AT8 staining. RESULTS: P301S tau mice had significantly decreased rapid eye movement (REM) sleep at 9 months of age and decreased REM and non‐REM (NREM) sleep as well as increased wakefulness at 11 months. Sleep loss was characterized by fewer wake, REM, and NREM bouts, increased wake bout duration, and decreased sleep bout duration. Decreased REM and NREM sleep was associated with increased brainstem tau pathology in the sublaterodorsal area and parafacial zone, respectively. P301S mice also showed increased EEG power at 6 and 9 months of age and decreased power at 11 months. Decreased EEG power was associated with decreased cortical volume. Despite sleep disturbances, P301S mice maintained homeostatic response to sleep deprivation. INTERPRETATION: Our results indicate that tau pathology is associated with sleep disturbances that worsen with age and these changes may be related to tau pathology in brainstem sleep regulating regions as well as neurodegeneration. Tau‐induced sleep changes could affect disease progression and be a marker for therapeutic efficacy in this and other tauopathy models

Evaluation of the soil moisture prediction accuracy of a space radar using simulation techniques

Image simulation techniques were employed to generate synthetic aperture radar images of a 17.7 km x 19.3 km test site located east of Lawrence, Kansas. The simulations were performed for a space SAR at an orbital altitude of 600 km, with the following sensor parameters: frequency = 4.75 GHz, polarization = HH, and angle of incidence range = 7 deg to 22 deg from nadir. Three sets of images were produced corresponding to three different spatial resolutions; 20 m x 20 m with 12 looks, 100 m x 100 m with 23 looks, and 1 km x 1 km with 1000 looks. Each set consisted of images for four different soil moisture distributions across the test site. Results indicate that, for the agricultural portion of the test site, the soil moisture in about 90% of the pixels can be predicted with an accuracy of = + or - 20% of field capacity. Among the three spatial resolutions, the 1 km x 1 km resolution gave the best results for most cases, however, for very dry soil conditions, the 100 m x 100 m resolution was slightly superior

Targeting tauopathy with engineered tau-degrading intrabodies

BACKGROUND: The accumulation of pathological tau is the main component of neurofibrillary tangles and other tau aggregates in several neurodegenerative diseases, referred to as tauopathies. Recently, immunotherapeutic approaches targeting tau have been demonstrated to be beneficial in decreasing tauopathy in animal models. We previously found that passive immunotherapy with anti-tau antibody to human tau or expression of an anti-tau secreted single-chain variable fragment (scFv) in the central nervous system of a mouse model of tauopathy decreased but did not remove all tau-associated pathology. Although these and other studies demonstrate that conventional immunotherapeutic approaches targeting tau can influence tau pathogenesis, the majority of pathological tau remains in the cytosol of cells, not typically accessible to an extracellular antibody. Therefore, we reasoned targeting intracellular tau might be more efficacious in preventing or decreasing tauopathy. METHODS: By utilizing our anti-tau scFv, we generated anti-tau intrabodies for the expression in the cytosol of neurons. To enhance the degradation capacity of conventional intrabodies, we engineered chimeric anti-tau intrabodies fused to ubiquitin harboring distinct mutations that shuttle intracellular tau for either the proteasome or lysosomal mediated degradation. To evaluate the efficacy in delaying or eliminating tauopathy, we expressed our tau degrading intrabodies or controls in human tau transgenic mice by adeno-associated virus prior to overt tau pathology and after tau deposition. RESULTS: Our results demonstrate, the expression of chimeric anti-tau intrabodies significantly reduce tau protein levels in primary neuronal cultures expression human tau relative to a non-modified anti-tau intrabody. We found the expression of engineered tau-degrading intrabodies destined for proteasomal-mediated degradation are more effective in delaying or eliminating tauopathy than a conventional intrabody in aged human tau transgenic mice. CONCLUSION: This study, harnesses the strength of intrabodies that are amendable for targeting specific domains or modifications with the cell-intrinsic mechanisms that regulate protein degradation providing a new immunotherapeutic approach with potentially improved efficacy