A human iPSC-derived hepatocyte screen identifies compounds that inhibit production of Apolipoprotein B.

Familial hypercholesterolemia (FH) patients suffer from excessively high levels of Low Density Lipoprotein Cholesterol (LDL-C), which can cause severe cardiovascular disease. Statins, bile acid sequestrants, PCSK9 inhibitors, and cholesterol absorption inhibitors are all inefficient at treating FH patients with homozygous LDLR gene mutations (hoFH). Drugs approved for hoFH treatment control lipoprotein production by regulating steady-state Apolipoprotein B (apoB) levels. Unfortunately, these drugs have side effects including accumulation of liver triglycerides, hepatic steatosis, and elevated liver enzyme levels. To identify safer compounds, we used an iPSC-derived hepatocyte platform to screen a structurally representative set of 10,000 small molecules from a proprietary library of 130,000 compounds. The screen revealed molecules that could reduce the secretion of apoB from cultured hepatocytes and from humanized livers in mice. These small molecules are highly effective, do not cause abnormal lipid accumulation, and share a chemical structure that is distinct from any known cholesterol lowering drug.

Magnetic resonance imaging reveals microemboli-mediated pathological changes in brain microstructure in diabetic rats: relevance to vascular cognitive impairment/dementia.

Diabetes doubles the risk of vascular cognitive impairment, but the underlying reasons remain unclear. In the present study, we determined the temporal and spatial changes in the brain structure after microemboli (ME) injection using diffusion MRI (dMRI). Control and diabetic rats received cholesterol crystal ME (40-70 µm) injections. Cognitive tests were followed up to 16 weeks, while dMRI scans were performed at baseline and 12 weeks post-ME. The novel object recognition test had a lower d2 recognition index along with a decrease in spontaneous alternations in the Y maze test in diabetic rats with ME. dMRI showed that ME injection caused infarction in two diabetic animals (n=5) but none in controls (n=6). In diabetes, radial diffusivity (DR) was increased while fractional anisotropy (FA) was decreased in the cortex, indicating loss of tissue integrity and edema. In the dorsal hippocampus, mean diffusivity (MD), axial diffusivity (DA), and DR were significantly increased, indicating loss of axons and myelin damage. Histological analyses confirmed more tissue damage and microglial activation in diabetic rats with ME. These results suggest that ME injury and associated cerebrovascular dysfunction are greater in diabetes, which may cause cognitive deficits. Strategies to improve vascular function can be a preventive and therapeutic approach for vascular cognitive impairment.

Drosophila Tet Is Required for Maintaining Glial Homeostasis in Developing and Adult Fly Brains.

Ten-eleven translocation (TET) proteins are crucial epigenetic regulators highly conserved in multicellular organisms. TETs' enzymatic function in demethylating 5-methyl cytosine in DNA is required for proper development and TETs are frequently mutated in cancer. Recently, Drosophila melanogaster Tet (dTet) was shown to be highly expressed in developing fly brains and discovered to play an important role in brain and muscle development as well as fly behavior. Furthermore, dTet was shown to have different substrate specificity compared with mammals. However, the exact role dTet plays in glial cells and how ectopic TET expression in glial cells contributes to tumorigenesis and glioma is still not clear. Here, we report a novel role for dTet specifically in glial cell organization and number. We show that loss of dTet affects the organization of a specific glia population in the optic lobe, the "optic chiasm" glia. Additionally, we find irregularities in axon patterns in the ventral nerve cord (VNC) both, in the midline and longitudinal axons. These morphologic glia and axonal defects were accompanied by locomotor defects in developing larvae escalating to immobility in adult flies. Furthermore, glia homeostasis was disturbed in dTet-deficient brains manifesting in gain of glial cell numbers and increased proliferation. Finally, we establish a Drosophila model to understand the impact of human TET3 in glia and find that ectopic expression of hTET3 in dTet-expressing cells causes glia expansion in larval brains and affects sleep/rest behavior and the circadian clock in adult flies.

Diabetic rats are more susceptible to cognitive decline in a model of microemboli-mediated vascular contributions to cognitive impairment and dementia.

Vascular disease plays an important role in all kinds of cognitive impairment and dementia. Diabetes increases the risk of vascular disease and dementia. However, it is not clear how existing vascular disease in the brain accelerates the development of small vessel disease and promotes cognitive dysfunction in diabetes. We used microemboli (ME) injection model in the current study to test the hypothesis that cerebrovascular dysfunction in diabetes facilitates entrapment of ME leading to inflammation and cognitive decline. We investigated cognitive function, axonal/white matter (WM) changes, neurovascular coupling, and microglial activation in control and diabetic male and female Wistar rats subjected to sham or low/high dose ME injection. Diabetic male animals had cognitive deficits, WM demyelination and greater microglial activation than the control animals even at baseline. Functional hyperemia gradually declined in diabetic male animals after ME injection. Both low and high ME injection worsened WM damage and increased microglial activation in diabetic male and female animals. Low ME did not cause cognitive decline in controls, while promoting learning/memory deficits in diabetic female rats and no further decline in diabetic male animals. High ME led to cognitive decline in control male rats and exacerbated the deficits in diabetic cohort. These results suggest that the existing cerebrovascular dysfunction in diabetes may facilitate ME-mediated demyelination leading to cognitive decline. It is important to integrate comorbidities/sex as a biological variable into experimental models for the development of preventive or therapeutic targets.