a-visual-approach-for-inducing-dolichoectasia-mice-to-model-large

A Visual Approach for Inducing Dolichoectasia in Mice to Model Large Vessel-Mediated Cerebrovascular Dysfunction

The blood-brain (BBB) is a crucial system that regulates selective brain circulation with the periphery, as an example, allowing necessary nutrients to ...

University of Toronto

Metallothionein III (MT-III) is a functionally distinct member of the metallothionein family that displays neuroinhibitory activity and is involved in the repair of neuronal damage. Altered expression levels of MT-III have been observed in Alzheimer's disease (AD) which has led to suggestions that it could be a mitigating factor in AD-related neuronal dysfunction. However, conflicting results have been reported on this issue which may be due to methodological differences and/or sampling size. In the current study, we have assessed MT-III expression in a large number of AD cases through the quantification of mRNA as well as by immunohistochemistry and Western blotting using an MT-III specific antibody. The results of this comprehensive study indicate that the mononucleosome DNA encoding MT-III is occluded preventing transcription and that message levels are reduced by approximately 30%. In addition, protein levels were specifically decreased by approximately 55% in temporal cortex. These data support the conclusion that MT-III is significantly downregulated in AD and may contribute to the loss of its protective effects and/or repair functions that lead to an exacerbation of the pathogenic processes.

Metallothionein III is reduced in Alzheimer's disease.

The zinc-binding protein S100beta has been identified as an interacting partner with the microtubule-associated protein tau. Both proteins are individually affected in Alzheimer's disease (AD). S100beta, is overexpressed in the disease, whereas hyperphosphorylated tau constitutes the primary component of neurofibrillary tangles. In this study, we examine factors that modulate their binding and the potential role the complex may play in AD pathogenesis. Zinc was identified as a critical component in the binding process and a primary modulator of S100beta-associated cellular responses. Abnormally phosphorylated tau extracted from AD tissue displayed a dramatically reduced capacity to bind S100beta, which was restored by pretreatment with alkaline phosphatase. In differentiated SH-SY5Y cells, exogenous S100beta was internalized and colocalized with tau consistent with an intracellular association. This was enhanced by the addition of zinc and eliminated by divalent metal chelators. S100beta uptake was also accompanied by extensive neurite outgrowth that may be mediated by its interaction with tau. S100beta-tau binding may represent a key pathway for neurite development, possibly through S100beta modulation of tau phosphorylation and/or functional stabilization of microtubules and process formation. S100beta-tau interaction may be disrupted by hyperphosphorylation and/or imbalances in zinc metabolism, and this may contribute to the neurite dystrophy associated with AD.

Wai Huang Yu

Department of Pharmacology and Toxicology

University of Toronto

A Visual Approach for Inducing Dolichoectasia in Mice to Model Large Vessel-Mediated Cerebrovascular Dysfunction

Wai Huang Yu

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Pharmacology and Toxicology

University of Toronto

A Visual Approach for Inducing Dolichoectasia in Mice to Model Large Vessel-Mediated Cerebrovascular Dysfunction

Department of Pharmacology and Toxicology