Search bioRxivSearch

Biology subjects

Dierks, T.

Publications and source records attributed to Dierks, T..

2 recordsLinked to original sources

Functional connectivity alterations of the temporal lobe and hippocampus in semantic dementia and Alzheimer’s disease

The severe semantic memory impairments in semantic dementia have been attributed to a pronounced atrophy and functional disruption of the anterior temporal lobes. In contrast, the medial and posterior temporal lobe damage predominantly found in patients with Alzheimers disease has been associated with episodic memory disturbance. However, the two dementia subtypes share hippocampal deterioration, despite a relatively spared episodic memory in semantic dementia. To gain more insight into the mutual and divergent functional alterations seen in Alzheimers disease and semantic dementia, we assessed the differences in intrinsic functional connectivity between temporal lobe regions in patients with Alzheimers disease (n = 16), semantic dementia patients from two international sites (n = 23), and healthy controls (n = 17). In an exploratory study, we used a functional parcellation of the temporal cortex to extract time series. The Alzheimers disease group showed a single connection with reduced functional connectivity as compared to the controls. This connection was located between the right orbitofrontal cortex and the right anterior temporal lobe. In contrast, functional connectivity was decreased in the semantic dementia group in six connections, mainly involving the hippocampus, lingual gyrus, temporal pole, and orbitofrontal cortex. We identified a common pathway with semantic dementia, since the functional connectivity between the right anterior temporal lobe and the right orbitofrontal cortex was reduced in both types of dementia. This might be related to social knowledge deficits as part of semantic memory decline. However, such interpretations are preferably made in the context of all disease-specific semantic impairments and functional connectivity changes. Despite some limitations owed to the two database sites, this study provides a first preliminary picture of the brains functional dysconnectivity in Alzheimers disease and semantic dementia. Future studies are needed to replicate findings of such a common pathway with matched diagnosis, neuropsychological, and data MRI acquisition procedures.

neuroscience

Genetically modified human type II collagen for N- and C-terminal covalent tagging

Collagen is the predominant structural protein in vertebrates, where it contributes to connective tissues and the extracellular matrix; it is also widely used in biomaterials and tissue engineering. Dysfunction of this protein and its processing can lead to a wide variety of developmental disorders and connective tissue diseases. Recombinantly engineering the protein is challenging due to posttranslational modifications generally required for its stability and secretion from cells. Introducing end labels into the protein is problematic, because the N- and C-termini of the physiologically relevant tropocollagen lie internal to the initially flanking N- and C-propeptide sequences. Here, we introduce mutations into human type II procollagen in a manner that address these concerns, and purify the recombinant protein from a stably transfected HT1080 human fibrosarcoma cell line. Our approach introduces chemically addressable groups into the N- and Ctelopeptide termini of tropocollagen. Simultaneous overexpression of formylglycine generating enzyme (FGE) allows the endogenous production of an aldehyde tag in a defined, substituted sequence in the N-terminus of the mutated collagen, while the C-terminus of each chain presents a sulfhydryl group from an introduced cysteine. These modifications are designed to enable specific covalent end-labelling of collagen. We find that the doubly-mutated protein folds and is secreted from cells, while higher-order assembly into well-ordered collagen fibrils is demonstrated through transmission electron microscopy. Chemical tagging of thiols is successful, however background from endogenous aldehydes present in wildtype collagen has thus far obscured the desired specific N-terminal labelling. Strategies to overcome this challenge are proposed.

biochemistry