Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme

sorLA is a recently identified neuronal receptor for amyloid precursor protein (APP) that is known to interact with APP and affect its intracellular transport and processing. Decreased levels of sorLA in the brain of Alzheimer's disease (AD) patients and elevated levels of amyloid-beta peptide (Abeta) in sorLA-deficient mice point to the importance of the receptor in this neurodegenerative disorder. We analyzed APP cleavage in an APP-shedding assay and found that both sorLA and, surprisingly, a sorLA tail construct inhibited APP cleavage in a beta-site APP-cleaving enzyme (BACE)-dependent manner. In line with this finding, sorLA and the sorLA tail significantly reduced secreted Abeta levels when BACE was overexpressed, suggesting that sorLA influences beta-cleavage. To understand the effect of sorLA on APP cleavage by BACE, we analyzed whether sorLA interacts with APP and/or BACE. Because both full-length sorLA and sorLA C-terminal tail constructs were functionally relevant for APP processing, we analyzed sorLA-APP for a potential cytoplasmatic interaction domain. sorLA and C99 coimmunoprecipitated, pointing toward the existence of a new cytoplasmatic interaction site between sorLA and APP. Moreover, sorLA and BACE also coimmunoprecipitate. Thus, sorLA interacts both with BACE and APP and might therefore directly affect BACE-APP complex formation. To test whether sorLA impacts BACE-APP interactions, we used a fluorescence resonance energy transfer assay to evaluate BACE-APP interactions in cells. We discovered that sorLA significantly reduced BACE-APP interactions in Golgi. We postulate that sorLA acts as a trafficking receptor that prevents BACE-APP interactions and hence BACE cleavage of APP

Different tau species lead to heterogeneous tau pathology propagation and misfolding.

Tauopathies are a heterogeneous group of pathologies characterized by tau aggregation inside neurons. Most of them are sporadic but certain tauopathies rely on tau gene (MAPT) mutations. They particularly differ from one to another by their different neuropathological signatures e.g. lesion shapes, regions affected and molecular composition of aggregates. Six isoforms of tau exist, but they do not all co-aggregate in each tauopathy but rather have a unique signature for each one. In some tauopathies such as Alzheimer's disease (AD), tau protein aggregation follows stereotypical anatomical stages. Recent data suggest that this progression is due to an active process of tau protein propagation from neuron-to-neuron. We wondered how tau isoforms or mutations could influence the process of tau aggregation and tau propagation. In human neuropathological material, we found that MAPT mutations induce a faster misfolding compared to tau found in sporadic AD patients. In the rat brain, we observed cell-to-cell transfer of non-pathological tau species irrespective of the tested isoform or presence of a mutation. By contrast, we found that the species of tau impact the propagation of tau pathology markers such as hyperphosphorylation and misfolding. Indeed, misfolding and hyperphosphorylated tau proteins do not spread at the same rate when tau is mutated, or the isoform composition is modified. These results clearly argue for the existence of specific folding properties of tau depending on isoforms or mutations impacting the behavior of pathological tau species

Designing out Medical Error: An Interdisciplinary Approach to the Design of Healthcare Equipment

Medical error is an internationally recognised problem, with major financial and human costs (Gray; 2003, de Vries; et.al. 2008). The design of hospital equipment, devices and environments can contribute to the problem. Clinical staff often have to cope with confusing interfaces and equipment, making their tasks difficult and potentially dangerous. There are calls to rethink the approach to design in healthcare. Design should acknowledge the real world issues users face in the hospital environment. A collaborative approach is required to understand these issues, (Karsh & Scanlon, 2007). This paper outlines the methodologies used in two interdisciplinary case study projects, revealing the importance of a clear set of working methods and detailing the approach taken at each point. The resulting designs aim to better support healthcare processes, reducing the instance of medical error and ultimately saving lives

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Anticholinesterase and Antioxidant Activities of Spilanthes filicaulis Whole Plant Extracts for the Management of Alzheimer’s Disease

Background: Spilanthes filicaulis is a tropical herb implicated as a memory enhancer in ethnomedicine. Objective: The study investigated acetyl/butyryl cholinesterase inhibitory and antioxidant activities of different extracts of S. filicaulis whole plant and correlated them to its phytochemical constituents. Methods: The powdered whole plant was successively extracted with n-hexane, ethyl acetate and methanol. Acetyl cholinesterase (AChE) and Butyryl cholinesterase (BuChE) inhibitory activity were evaluated by Ellman colorimetry assay. Antioxidant activity was tested using 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, ferric reducing power and nitric oxide scavenging assays. Total phenolic, flavonoid and tannin were estimated using standard methods. Correlation was determined using Quest Graph™ Regression Calculator. Results: Various extracts exhibited concentration-dependent AChE and BuChE inhibitory activity with ethyl acetate extract being the highest with IC50 of 0.77 μg/mL and 0.92 μg/mL for AChE and BuChE respectively. The ethyl acetate extract also showed the highest reducing power when compared with the other extracts. The methanol extract had slightly higher phenolic and flavonoid content and showed the highest DPPH radical scavenging effect. DPPH scavenging, AChE and BuChE inhibition had high correlation with the total flavonoid content with R2 values of 1.00, 0.800 and 0.992 respectively while nitric oxide scavenging had high correlation with phenolics and tannins with R2 = 0.942 and 0.806 respectively. Conclusion: These results show that the extracts of the whole plant of S. filicaulis possess significant AChE/BuChE inhibitory and antioxidant properties, mostly due to its flavonoid content, suggesting the possible use of the plant in neurodegenerative diseases such as AD

Soluble forms of tau are toxic in Alzheimer's disease

Accumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer Disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer’s disease and other tauopathies

Analysis of shared heritability in common disorders of the brain

Paroxysmal Cerebral Disorder