Alzheimer's disease: synapses gone cold

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by insidious cognitive decline and memory dysfunction. Synapse loss is the best pathological correlate of cognitive decline in AD and mounting evidence suggests that AD is primarily a disease of synaptic dysfunction. Soluble oligomeric forms of amyloid beta (Aβ), the peptide that aggregates to form senile plaques in the brain of AD patients, have been shown to be toxic to neuronal synapses both in vitro and in vivo. Aβ oligomers inhibit long-term potentiation (LTP) and facilitate long-term depression (LTD), electrophysiological correlates of memory formation. Furthermore, oligomeric Aβ has also been shown to induce synapse loss and cognitive impairment in animals. The molecular underpinnings of these observations are now being elucidated, and may provide clear therapeutic targets for effectively treating the disease. Here, we review recent findings concerning AD pathogenesis with a particular focus on how Aβ impacts synapses

Assessment of safety and efficacy of Karallief® Easy ClimbTM, an herbal extract blend for supporting joint health: a double-blind, placebo-controlled, randomized clinical trial

Background: Osteoarthritis is common among the aging population worldwide. The current techniques to manage osteoarthritis focus on relieving pain and slowing the progression of the disease. Herbal or natural supplements have shown promise in achieving both these treatment goals. Two new proprietary herbal extract blends, Karallief® Easy ClimbTM (KEC) and herbal extracts with glucosamine (HEG), are combinations of several natural products shown to be effective in the treatment of knee osteoarthritis. The current study tested the efficacy and safety of KEC and HEG versus a placebo control.Methods: This is a randomized, double-blind and placebo-controlled study. A total of 120 patients were divided into 3 groups and were given KEC, HEG and Placebo in the ratio 1:1:1. Treatment results were assessed using the 30 second chair stand test, WOMAC test, knee flexion test and joint space measurement using X-rays of the knee joint.Results: The study found that the herbal supplements HEG and KEC significantly reduced osteoarthritis-related knee pain and increased joint mobility and were safe to use during 120 days of treatment. Both supplements resulted in an improvement in the 30 second chair stand test results, WOMAC pain scores, knee flexion, and joint space width as measured by X-ray, as compared to the placebo.Conclusions: Natural supplements such as HEG and KEC improve knee osteoarthritis symptoms and can be a safe and effective treatment option for patients with osteoarthritis

Studying synapses in human brain with array tomography and electron microscopy

Postmortem studies of synapses in human brain are problematic due to the axial resolution limit of light microscopy and the difficulty preserving and analyzing ultrastructure with electron microscopy. Array tomography overcomes these problems by embedding autopsy tissue in resin and cutting ribbons of ultrathin serial sections. Ribbons are imaged with immunofluorescence, allowing high-throughput imaging of tens of thousands of synapses to assess synapse density and protein composition. The protocol takes approximately 3 days per case, excluding image analysis, which is done at the end of the study. Parallel processing for transmission electron microscopy (TEM) using a protocol modified to preserve structure in human samples allows complimentary ultrastructural studies. Incorporation of array tomography and TEM into brain banking is a potent way of phenotyping synapses in well-characterized clinical cohorts to develop clinico-pathological correlations at the synapse level. This will be important for research in neurodegenerative disease, developmental diseases, and psychiatric illness

Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer's disease brain

Neurofibrillary tangles (NFT), intracellular inclusions of abnormal fibrillar forms of microtubule associated protein tau, accumulate in Alzheimer's disease (AD) and other tauopathies and are believed to cause neuronal dysfunction, but the mechanism of tau-mediated toxicity are uncertain. Tau overexpression in cell culture impairs localization and trafficking of organelles. Here we tested the hypothesis that, in the intact brain, changes in mitochondrial distribution occur secondary to pathological changes in tau. Array tomography, a high-resolution imaging technique, was used to examine mitochondria in the reversible transgenic (rTg)4510, a regulatable transgenic, mouse model and AD brain tissue. Mitochondrial distribution is progressively disrupted with age in rTg4510 brain, particularly in somata and neurites containing Alz50-positive tau aggregates. Suppression of soluble tau expression with doxycycline resulted in complete recovery of mitochondrial distribution, despite the continued presence of aggregated tau. The effect on mitochondrial distribution occurs without concomitant alterations in neuropil mitochondrial size, as assessed by both array tomography and electron microscopy. Similar mitochondrial localization alterations were also observed in human AD tissue in Alz50+ neurons, confirming the relevance of tau to mitochondrial trafficking observed in this animal model. Because abnormalities reverted to normal if soluble tau was suppressed in rTg4510 mice, even in the continued presence of fibrillar tau inclusions, we suggest that soluble tau plays an important role in mitochondrial abnormalities, which likely contribute to neuronal dysfunction in AD

Alzheimer's Therapeutics Targeting Amyloid Beta 1-42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

Amyloid beta (Abeta) 1–42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics

Are tangles as toxic as they look?

Neurofibrillary tangles are intracellular accumulations of hyperphosphorylated and misfolded tau protein characteristic of Alzheimer's disease and other tauopathies. Classic cross-sectional studies of Alzheimer patient brains showed associations of tangle accumulation with neuronal loss, synapse loss, and dementia, which led to the supposition that tangles are toxic to neurons. More recent advances in imaging techniques and mouse models have allowed the direct exploration of the question of toxicity of aggregated versus soluble tau and have surprisingly challenged the view of tangles as toxic species in the brain. Here, we review these recent experiments on the nature of the toxicity of tau with particular emphasis on our experiments imaging tangles in the intact brain through a cranial window, which allows observation of tangle formation and longitudinal imaging of the fate of tangle-bearing neurons. Neurofibrillary tangles (NFT) were first described in 1906 by Alois Alzheimer based on Bielschowsky silver staining of the brain of his demented patient Auguste D (Alzheimer 1907; Goedert and Spillantini 2006). These intraneuronal aggregates have subsequently been found to be composed primarily of hyperphosphorylated tau protein and are definitive pathological lesions not only in Alzheimer's disease but also in a class of neurodegenerative tauopathies (Goedert et al. 1988; Spires-Jones et al. 2009). NFT pathology in Alzheimer's disease (AD) correlates closely with cognitive decline and synapse and neuronal loss (Braak and Braak 1997; Bretteville and Planel 2008; Congdon and Duff 2008; Mocanu et al. 2008b; Spires-Jones et al. 2009). As a result, NFT have long been considered indicative of impending neuronal cell death. More recent evidence, however, opposes this classical view. Here we review evidence addressing the question of whether NFT cause structural or functional neuronal damage

Novel Technique for C1–2 Interlaminar Arthrodesis Utilizing a Modified Sonntag Loop-Suture Graft With Posterior C1–2 Fixation

Objective Conventional techniques for atlantoaxial fixation and fusion typically pass cables or wires underneath C1 lamina to secure the bone graft between the posterior elements of C1–2, which leads to complications such as cerebrospinal fluid (CSF) leak and neurological injury. With the evolution of fixation hardware, we propose a novel C1–2 fixation technique that avoids the morbidity and complications associated with sublaminar cables and wires. Methods This technique entails wedging and anchoring a structural iliac crest graft between C1 and C2 for interlaminar arthrodesis and securing it using a 0-Prolene suture at the time of C1 lateral mass and C2 pars interarticularis screw fixation. Results We identified 32 patients who underwent surgery for atlantoaxial with our technique. A 60% improvement in pain-related disability from preoperative baseline was demonstrated by Neck Disability Index (p<0.001). There were no neurologic deficits. Complications included 2 patients CSF leaks related to presenting trauma, 1 patient with surgical site infection, and 1 patient with transient dysphagia. The rate of radiographic atlantoaxial fusion was 96.8% at 6 months, with no evidence of instrumentation failure, graft dislodgement, or graft related complications. Conclusion We demonstrate a novel technique for C1–2 arthrodesis that is a safe and effective option for atlantoaxial fusion

Global incidence of brain and spinal tumors by geographic region and income level based on cancer registry data

While obtaining accurate estimates of tumor incidence volume is a difficult technical problem because it requires collating and analyzing data from dozens of world-wide sources curated under different conditions, our study aims to determine the global incidence of brain and spinal tumors. We analyzed 207 tumor registries on five continents, and calculated age-standardized rates to compare tumor incidence between geographic regions and income levels. Based on data available in current cancer registries, the apparent global incidence of malignant brain tumors was 4.25 cases per 100,000 person-years (95% CI [4.21-4.29]), and varied by region from 6.76 [6.71-6.80] in Europe to 2.81 [2.64-2.99] in Africa. Incidence also varied by World Bank income group, ranging from 6.29 [6.26-6.32] cases per 100,000 in high income countries (HICs), to 4.81 [4.77-4.86] in low and middle-income countries (LMICs). Malignant spinal tumors were much less frequent globally (0.098 [0.093-0.104]) and varied similarly by region and income group. The incidence of brain and spinal tumors varies by region and income group, although case ascertainment bias driven by limited resources in low income regions likely plays a role in variance. The burden of neurosurgical disease in LMICs is large, and similar in scale to HICs