Exogenous Aß seeds induce Aß depositions in the blood vessels rather than the brain parenchyma, independently of Aß strain-specific information.

Little is known about the effects of parenchymal or vascular amyloid ß peptide (Aß) deposition in the brain. We hypothesized that Aß strain-specific information defines whether Aß deposits on the brain parenchyma or blood vessels. We investigated 12 autopsied patients with different severities of Aß plaques and cerebral amyloid angiopathy (CAA), and performed a seeding study using an Alzheimer's disease (AD) mouse model in which brain homogenates derived from the autopsied patients were injected intracerebrally. Based on the predominant pathological features, we classified the autopsied patients into four groups: AD, CAA, AD + CAA, and less Aß. One year after the injection, the pathological and biochemical features of Aß in the autopsied human brains were not preserved in the human brain extract-injected mice. The CAA counts in the mice injected with all four types of human brain extracts were significantly higher than those in mice injected with PBS. Interestingly, parenchymal and vascular Aß depositions were observed in the mice that were injected with the human brain homogenate from the less Aß group. The Aß and CAA seeding activities, which had significant positive correlations with the Aß oligomer ratio in the human brain extracts, were significantly higher in the human brain homogenate from the less Aß group than in the other three groups. These results indicate that exogenous Aß seeds from different Aß pathologies induced Aß deposition in the blood vessels rather than the brain parenchyma without being influenced by Aß strain-specific information, which might be why CAA is a predominant feature of Aß pathology in iatrogenic transmission cases. Furthermore, our results suggest that iatrogenic transmission of Aß pathology might occur due to contamination of brain tissues from patients with little Aß pathology, and the development of inactivation methods for Aß seeding activity to prevent iatrogenic transmission is urgently required.

Evx2-Hoxd13 intergenic region restricts enhancer association to Hoxd13 promoter.

Expression of Hox genes is tightly regulated in spatial and temporal domains. Evx2 is located next to Hoxd13 within 8 kb on the opposite DNA strand. Early in development, the pattern of Hoxd13 expression resembles that of Evx2 in limb and genital buds. After 10 dpc, however, Evx2 begins to be expressed in CNS as well. We analyzed the region responsible for these differences using ES cell techniques, and found that the intergenic region between Evx2 and Hoxd13 behaves as a boundary element that functions differentially in space and time, specifically in the development of limbs, genital bud, and brain. This boundary element comprises a large sequence spanning several kilobases that can be divided into at least two units: a constitutive boundary element, which blocks transcription regulatory influences from the chromosomal environment, and a regulatory element, which controls the function of the constitutive boundary element in time and space.

Electrical stimulation modulates fate determination of differentiating embryonic stem cells.

A clear understanding of cell fate regulation during differentiation is key in successfully using stem cells for therapeutic applications. Here, we report that mild electrical stimulation strongly influences embryonic stem cells to assume a neuronal fate. Although the resulting neuronal cells showed no sign of specific terminal differentiation in culture, they showed potential to differentiate into various types of neurons in vivo, and, in adult mice, contributed to the injured spinal cord as neuronal cells. Induction of calcium ion influx is significant in this differentiation system. This phenomenon opens up possibilities for understanding novel mechanisms underlying cellular differentiation and early development, and, perhaps more importantly, suggests possibilities for treatments in medical contexts.