Hypothesis: Entrapment of lipoprotein particles in the brain causes Alzheimer’s disease

We present for consideration a hypothesis that impaired movement of lipoprotein particles in the extracellular space in the brain in ageing is central to and causes all the key pathophysiological features of Alzheimer’s disease (AD). The role of lipoprotein particles is to transport cholesterol from glial cells, where it is synthesised, to neurons, which require cholesterol for synaptic plasticity. The lipoprotein particles have a cholesterol-containing hydrophobic core, in which amyloid-β (Aβ) can be solubilised. The core is surrounded by a hydrophilic surface containing apolipoprotein E (APOE) which, as neurons bear receptors for APOE, determines the destination of the particles. The problem arises because the extracellular space is a narrow cleft, barely wider than the lipoprotein particles themselves, which they have to navigate in order to perform their crucial cholesterol-transporting function. We explain how lipoprotein particles could become trapped in the ageing extracellular matrix and that this primary abnormality results in reduced delivery of cholesterol to neurons leading to impaired synaptic plasticity, crucial for learning and memory. It can also explain extracellular Aβ accumulation, to which a microglial response generates a neurotoxic reaction, and intraneuronal tau aggregation, each of which exacerbate the problem. All these players have been known for many years to be important in Alzheimer’s pathogenesis but a single unifying mechanism to explain how they are linked has been lacking. This proposed mechanism, with entrapment of lipoproteins particles as key to the development of AD, can explain the failure of so many clinical trials and points out new directions to be taken

Constituency of Rage: Strange gods, 'realishness,' and the rise of the Hysterical Right

The advent of the Tea Party movement shortly after the inauguration of Barack Obama signaled the beginning of the Republican Party’s rapid shift to the far right. By exploiting the Tea Party as a ‘constituency of rage,’ and anti-Obama sentiment in general, the Republicans undertook a deliberate project of legislative obstruction for purely political and ideological reasons, resulting in an unprecedented gridlock in Congress. That a major political party should undergo such a dramatic and far-reaching change in only four years is remarkable. Meanwhile, a certain collective hysteria became more and more evident on the Right, together with a rejection of facts, science, and even reality. This paper establishes a conceptual model and an accompanying social mechanics to provide a new critical perspective through which such changes can be analyzed and understood. This model uses an extended relativistic physics analogy of ‘sociopolitical spacetime’ in order to unify hysteria with the influence of ‘strange gods’ in the political media (such as Sarah Palin, Glenn Beck, and Rush Limbaugh), the convergence of which creates ‘warps’ in which Tea Partiers and Republicans experience a collective phenomenon of ‘realishness’—the ontological and phenomenological analogue to Stephen Colbert’s ‘truthiness.’ Finally, I provide my own assessment of the state of right-wing politics in the Obama era, and what this suggests for the future of social conservatism in the twenty-first century

The heme-hemopexin scavenging system is active in the brain, and associates with outcome after subarachnoid hemorrhage

Background and Purpose – Long-term outcome after subarachnoid hemorrhage (SAH) is potentially linked to cytotoxic heme. Free heme is bound by hemopexin (Hpx) and rapidly scavenged by CD91. We hypothesized that heme scavenging in the brain would be associated with outcome after haemorrhage. Methods - Using cerebrospinal fluid (CSF) and tissue from SAH patients and control individuals, the activity of the intracranial CD91-Hpx system was examined using enzyme-linked immunoassays, ultra-high performance liquid chromatography and immunohistochemistry. Results - In control individuals, CSF Hpx was mainly synthesized intrathecally. After SAH, CSF Hpx was high in one-third of cases, and these patients had a higher probability of delayed cerebral ischaemia and poorer neurological outcome. The intracranial CD91-Hpx system was active after SAH since CD91 positively correlated with iron deposition in brain tissue. Heme-Hpx uptake saturated rapidly after SAH, since bound heme accumulated early in the CSF. When the blood-brain barrier was compromised following SAH, serum Hpx level was lower, suggesting heme transfer to the circulation for peripheral CD91 scavenging. Conclusions - The CD91-heme-Hpx scavenging system is important after SAH and merits further study as a potential prognostic marker and therapeutic target

Cellular Models of Aggregation-Dependent Template-Directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer's Disease

Copyright © 2015, The American Society for Biochemistry and Molecular Biology. Acknowledgements-We thank Drs Timo Rager and Rolf Hilfiker (Solvias, Switzerland) for polymorph analyses.Peer reviewedPublisher PD

Localized microglia dysregulation impairs central nervous system myelination in development

Myelination of neuronal axons is a critical aspect of central nervous system development and function. However, the fundamental cellular and molecular mechanisms influencing human developmental myelination and its failure are not fully understood. Here, we used digital spatial transcriptomics of a rare bank of human developing white matter to uncover that a localized dysregulated innate immune response is associated with impeded myelination. We identified that poorly myelinating areas have a distinct signature of Type II interferon signalling in microglia/macrophages, relative to adjacent myelinating areas. This is associated with a surprising increase in mature oligodendrocytes, which fail to form myelin processes appropriately. We functionally link these findings by showing that conditioned media from interferon-stimulated microglia is sufficient to dysregulate myelin process formation by oligodendrocytes in culture. We identify the Type II interferon inducer, Osteopontin (SPP1), as being upregulated in poorly myelinating brains, indicating a potential biomarker. Our results reveal the importance of microglia-mature oligodendrocyte interaction and interferon signaling in regulating myelination of the developing human brain.</p

Improving the quality of weekend medical handover on non-receiving medical hospital wards

INTRODUCTION: Handover is the system by which the responsibility for immediate and ongoing care is transferred between healthcare professionals and can be an area of risk. The Royal College of Physicians (RCP) has recommended improvement and standardisation of handover. Locally, national training surveys have reported poor feedback regarding handover at Glasgow Royal Infirmary. AIM: To improve and standardise handover from weekday to weekend teams. METHODS: The Plan–Do–Study–Act (PDSA) quality improvement framework was used. Interventions were derived from a driver diagram after consultation with relevant stakeholders. Four PDSA cycles were completed over a 4-month period: PDSA cycle 1—Introduction of standardised paper form on three wards. PDSA cycle 2—Introduction of electronic handover system on three wards. PDSA cycle 3—Expansion of electronic handover to seven wards. PDSA cycle 4—Expansion of electronic handover to all non-receiving medical wards. The outcome of interest was the percentage of patients with full information handed over based on a six-point scale derived from the RCP. Data were collected weekly throughout the study period. RESULTS: 18 data collection exercises were performed including 525 patients. During the initial phase there was an improvement in handover quality with 0/28 (0%) at baseline having all six points completed compared with 13/48 (27%) with standardised paper form and 21/42 (50%) with the electronic system (p<0.001). When the electronic handover form was expanded to all wards, the increased quality was maintained, however, to a lesser extent compared with the initial wards. CONCLUSION: A standardised electronic handover system was successfully introduced to downstream medical wards over a short time period. This led to an in improvement in the quality of handover in the initial wards involved. When expanded to a greater number of wards there was still an improvement in quality but to a lesser degree