Faculty Bibliography

INTRODUCTION/BACKGROUND:Insulin resistance and type 2 diabetes mellitus (T2D) are associated with increased risk for cognitive impairment, Alzheimer's disease (AD) and vascular dementia. SORCS1 encodes a protein-sorting molecule genetically linked to both T2D and AD. The association of SORCS1 with both AD and T2D is sexually dimorphic in humans, with both disease associations showing more robust effects in females. Based on published evidence that manipulation of the mouse genome combining multiple genes related to cerebral amyloidosis, to T2D, or both, might provide novel mouse models with exacerbated amyloid and/or diabetes phenotypes, we assessed memory, glucose homeostasis, and brain biochemistry and pathology in male and female wild-type, Sorcs1 -/-, APP/PSEN1, and Sorcs1 -/- X APP/PSEN1 mice. RESULTS:Male mice with either the APP/PSEN1 or Sorcs1 -/- genotype displayed earlier onset and persistent impairment in both learning behavior and glucose homeostasis. Unlike prior examples in the literature, the behavioral and metabolic abnormalities in male mice were not significantly exacerbated when the two disease model mice (Sorcs1 -/- models T2D; APP/PSEN1 models AD) were crossed. However, female Sorcs1 -/- X APP/PSEN1 mice exhibited worse metabolic dysfunction than Sorcs1 -/- knockout mice and worse memory than wild-type mice. The deletion of Sorcs1 from APP/PSEN1 mutant mice led to no obvious changes in brain levels of total or oligomeric amyloid-beta (Aβ) peptide. CONCLUSIONS:In general, unexpectedly, there was a trend for gene targeting of Sorcs1-/- to partially mitigate, not exacerbate, the metabolic and amyloid pathologies. These results indicate that crossing AD model mice and T2D model mice may not always cause exacerbation of both the amyloidosis phenotype and the metabolic phenotype and highlight the unexpected pitfalls of creating mixed models of disease.

INTRODUCTION:Epidemiologic studies have demonstrated an association between diabetes and dementia. Insulin signaling within the brain, in particular within the hypothalamus regulates carbohydrate, lipid, and branched chain amino acid (BCAA) metabolism in peripheral organs such as the liver and adipose tissue. We hypothesized that cerebral amyloidosis impairs central nervous system control of metabolism through disruption of insulin signaling in the hypothalamus, which dysregulates glucose and BCAA homeostasis resulting in increased susceptibility to diabetes. METHODS:We examined whether APP/PS1 mice exhibit increased susceptibility to aging or high-fat diet (HFD)-induced metabolic impairment using metabolic phenotyping and insulin-signaling studies. RESULTS:APP/PS1 mice were more susceptible to high-fat feeding and aging-induced metabolic dysregulation including disrupted BCAA homeostasis and exhibited impaired hypothalamic insulin signaling. DISCUSSION:Our data suggest that AD pathology increases susceptibility to diabetes due to impaired hypothalamic insulin signaling, and that plasma BCAA levels could serve as a biomarker of hypothalamic insulin action in patients with AD.

Previous National Council on Radiation Protection and Measurements (NCRP) publications have addressed the issues of risk and dose limitation in radiation protection and included guidance on specific organs and the lens of the eye. NCRP decided to prepare an updated commentary intended to enhance the previous recommendations provided in earlier reports. The NCRP Scientific Committee 1-23 (SC 1-23) is charged with preparing a commentary that will evaluate recent studies on the radiation dose response for the development of cataracts and also consider the type and severity of the cataracts as well as the dose rate; provide guidance on whether existing dose limits to the lens of the eye should be changed in the United States; and suggest research needs regarding radiation effects on and dose limits to the lens of the eye. A status of the ongoing work of SC 1-23 was presented at the Annual Meeting, "Changing Regulations and Radiation Guidance: What Does the Future Hold?" The following represents a synopsis of a few main points in the current draft commentary. It is likely that several changes will be forthcoming as SC 1-23 responds to subject matter expert review and develops a final document, expected by mid 2016.

PURPOSE OF REVIEW:Better tools are sorely needed for both the prevention and treatment of cardiovascular diseases, which account for more than one-third of the deaths in Western countries. MicroRNAs typically regulate the expression of several mRNAs involved in the same biological process. Therapeutic manipulation of miRNAs could restore the expression of multiple players within the same physiologic pathway, and ideally offer better curative outcomes than conventional approaches that target only one single player within the pathway. This review summarizes available studies on the prospective value of targeting miRNAs to prevent dyslipidemia and atherogenesis. RECENT FINDINGS:Silencing the expression of miRNAs that target key genes involved in lipoprotein metabolism in vivo with antisense oligonucleotides results in the expected de-repression of target mRNAs in liver and atherosclerotic plaques. However, the consequences of long-term antimiRNA treatment on both circulating lipoproteins and athero-protection are yet to be established. SUMMARY:A number of studies have demonstrated the efficacy of miRNA mimics and inhibitors as novel therapeutic tools for treating dyslipidemia and cardiovascular diseases. Nevertheless, concerns over unanticipated side-effects related to de-repression of additional targets should not be overlooked for miRNA-based therapies.

Recent discoveries have revealed that microRNAs (miRNAs) play a key role in the regulation of gene expression. In this review, we summarize the rapidly evolving knowledge about liver miRNAs (including miR-33, -33*, miR-223, -30c, -144, -148a, -24, -29, and -122) and their link to hepatic lipid metabolism, atherosclerosis and cardiovascular disease, non-alcoholic fatty liver disease, metabolic syndrome, and type-2 diabetes. With regards to its biomarker potential, the main focus is on miR-122 as the most abundant liver miRNA with exquisite tissue specificity. MiR-122 has been proposed to play a central role in the maintenance of lipid and glucose homeostasis and is consistently detectable in serum and plasma. This miRNA may therefore constitute a novel biomarker for cardiovascular and metabolic diseases.

In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis. The endothelium-specific genetic ablation of Alk1 in Ldlr-KO animals leads to less LDL uptake into the aortic endothelium, showing its physiological role in endothelial lipoprotein metabolism. In summary, identification of pathways mediating LDLR-independent uptake of LDL may provide unique opportunities to block the initiation of LDL accumulation in the vessel wall or augment hepatic LDLR-dependent clearance of LDL.

Almost every aspect of cryo electron microscopy (cryoEM) has been automated over the last few decades. One of the challenges that remains to be addressed is the robust and reliable preparation of vitrified specimens of suitable ice thickness. We present results from a new device for preparing vitrified samples. The successful use of the device is coupled to a new "self-blotting" grid that we have developed to provide a method for spreading a sample to a thin film without the use of externally applied filter paper. This new approach has the advantage of using small amounts of protein material, resulting in large areas of ice of a well defined thickness containing evenly distributed single particles. We believe that these methods will in the future result in a system for vitrifying grids that is completely automated.