Comprehensive Monosynaptic Rabies Virus Mapping of Host Connectivity with Neural Progenitor Grafts after Spinal Cord Injury.

Neural progenitor cells grafted to sites of spinal cord injury have supported electrophysiological and functional recovery in several studies. Mechanisms associated with graft-related improvements in outcome appear dependent on functional synaptic integration of graft and host systems, although the extent and diversity of synaptic integration of grafts with hosts are unknown. Using transgenic mouse spinal neural progenitor cell grafts expressing the TVA and G-protein components of the modified rabies virus system, we initiated monosynaptic tracing strictly from graft neurons placed in sites of cervical spinal cord injury. We find that graft neurons receive synaptic inputs from virtually every known host system that normally innervates the spinal cord, including numerous cortical, brainstem, spinal cord, and dorsal root ganglia inputs. Thus, implanted neural progenitor cells receive an extensive range of host neural inputs to the injury site, potentially enabling functional restoration across multiple systems

Injured adult motor and sensory axons regenerate into appropriate organotypic domains of neural progenitor grafts.

Neural progenitor cell (NPC) transplantation has high therapeutic potential in neurological disorders. Functional restoration may depend on the formation of reciprocal connections between host and graft. While it has been reported that axons extending out of neural grafts in the brain form contacts onto phenotypically appropriate host target regions, it is not known whether adult, injured host axons regenerating into NPC grafts also form appropriate connections. We report that spinal cord NPCs grafted into the injured adult rat spinal cord self-assemble organotypic, dorsal horn-like domains. These clusters are extensively innervated by regenerating adult host sensory axons and are avoided by corticospinal axons. Moreover, host axon regeneration into grafts increases significantly after enrichment with appropriate neuronal targets. Together, these findings demonstrate that injured adult axons retain the ability to recognize appropriate targets and avoid inappropriate targets within neural progenitor grafts, suggesting that restoration of complex circuitry after SCI may be achievable

Cognitive Testing, Neuroimaging, and Blood Biomarkers in the Development and Progression of Alzheimer's Disease

Gemstone Team BRAINAlzheimer’s disease (AD) is a progressive neurodegenerative disorder, characterized by significant loss of memory and cognitive dysfunction. It has a significant impact on an individual’s health and may financially and socially burden these individuals and their loved ones. Although the disease has been researched extensively, there is still no clear understanding of the proposed mechanisms behind the development of AD and factors aside from genetics which potentially influence the risk of developing AD. The purpose of this research is to compile and analyze data on cognitively healthy participants, participants with MCI, and participants with AD to better understand the importance of genetic risk and changes in cognitive function, bioimaging and biomarker levels, as recorded on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. There are complex and significant relationships among these three variable groups with genetics and time. Executive function scores in healthy participants and participants with MCI were decreased with age and increased with education. In participants with AD, scores decreased over time. Language scores in healthy participants decreased with age, increased with education and for women. In participants with MCI, scores decreased with risk and time, and there was an interaction between these two variables. They also decreased with age and increased with education. In participants with AD language scores decreased over time. Memory scores in healthy participants increase with time and education and for women. In participants with MCI, scores increased with education and decreased with risk and time, and there was an interaction between these two variables. For participants with AD, there was a decrease over time. Visuospatial ability scores in healthy participants decreased with education. In participants with MCI, scores decreased with genetic risk and increased with education. In participants with AD, scores decreased over time and increased with age. Left hippocampal volume in healthy participants decreased with time, age, and education, and is increased in women. In participants with MCI, volume decreased with risk, time, age, and education. In participants with AD, volume decreased with time and age. Right hippocampal volume in healthy participants decreased with time, age, and education. In participants with MCI, volume decreased with risk and time, and there was an interaction between these two variables. Volumes also decreased with age. For participants with AD, volume decreased with risk, time, and age. Total hippocampal volume in healthy participants decreased with time, age, and education, and was increased for women. There was also an interaction between risk and time. In participants with MCI, volumes decreased with risk and time, and there was an interaction between these two variables. Volumes also decreased with age and education. For participants with AD, volumes decreased with risk, time, and age. Aβ42 levels in healthy participants decreases with risk and increased with time. In participants with MCI, levels increased with time and age, and were lower in women. In participants with AD, levels increased with time. Aβ40 levels in healthy participants increased with time and were lower for women. For participants with MCI, levels increased with time and age, and were lower for women. In participants with AD, levels increased over time. The Aβ42/40 ratio in healthy participants decreased with risk and time, and decreased with time in participants with MCI. The findings give insight into AD development and contribute to a greater understanding of longitudinal changes in AD progression. In relation to the study of AD includes the perpetuation of racial inequalities. People of color have an increased risk of developing AD and are disproportionately affected by the disease, yet are severely underrepresented in most research studies, including the research collected in the ADNI database. Racial minorities also often do not have the same access to healthcare as white people, thus contributing to the decreased possibility of early detection and treatment of AD. Black Americans, specifically, often face socio-economic barriers, which further renders the burden of AD development and progression more serious for minority families. In order to promote awareness of AD among underrepresented communities, Team Brain virtually presented to the African American Health Program, a local community of minority elders, via virtual presentations. Overall, this research concluded that hippocampal atrophy and cognitive tests appear to be the most consistent factors in the progression of MCI and AD. The analysis of blood biomarkers produced inconclusive results. This research indicates a clear set of imaging and cognitive factors that can be used to create less invasive and novel diagnostic methods for AD as well as supports the need for further research on blood biomarkers to understand their relationship with cognitive decline and progression of AD

Endocrine remodelling of the adult intestine sustains reproduction in Drosophila.

The production of offspring is energetically costly and relies on incompletely understood mechanisms that generate a positive energy balance. In mothers of many species, changes in key energy-associated internal organs are common yet poorly characterised functionally and mechanistically. In this study, we show that, in adult Drosophila females, the midgut is dramatically remodelled to enhance reproductive output. In contrast to extant models, organ remodelling does not occur in response to increased nutrient intake and/or offspring demands, but rather precedes them. With spatially and temporally directed manipulations, we identify juvenile hormone (JH) as an anticipatory endocrine signal released after mating. Acting through intestinal bHLH-PAS domain proteins Methoprene-tolerant (Met) and Germ cell-expressed (Gce), JH signals directly to intestinal progenitors to yield a larger organ, and adjusts gene expression and sterol regulatory element-binding protein (SREBP) activity in enterocytes to support increased lipid metabolism. Our findings identify a metabolically significant paradigm of adult somatic organ remodelling linking hormonal signals, epithelial plasticity, and reproductive output. DOI: http://dx.doi.org/10.7554/eLife.06930.00

A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance

Damaged mitochondria pose a lethal threat to cells that necessitates their prompt removal. The currently recognized mechanism for disposal of mitochondria is autophagy, where damaged organelles are marked for disposal via ubiquitylation by Parkin. Here we report a novel pathway for mitochondrial elimination, in which these organelles undergo Parkin-dependent sequestration into Rab5-positive early endosomes via the ESCRT machinery. Following maturation, these endosomes deliver mitochondria to lysosomes for degradation. Although this endosomal pathway is activated by stressors that also activate mitochondrial autophagy, endosomal-mediated mitochondrial clearance is initiated before autophagy. The autophagy protein Beclin1 regulates activation of Rab5 and endosomal-mediated degradation of mitochondria, suggesting cross-talk between these two pathways. Abrogation of Rab5 function and the endosomal pathway results in the accumulation of stressed mitochondria and increases susceptibility to cell death in embryonic fibroblasts and cardiac myocytes. These data reveal a new mechanism for mitochondrial quality control mediated by Rab5 and early endosomes

Biomarker Research Applications in Alzheimer's Disease

Alzheimer’s Disease (AD) affects millions of older individuals and is a growing problem without an accessible diagnosis method, drug target for treatment, or model of the longitudinal progression of the disease. The project, led by University of Maryland Gemstone Team BRAIN, aims to determine how changes in memory, visuospatial ability, the plasma amyloid β 42/40 ratio, and the total hippocampal volume can be used to accurately predict the onset and progression of AD. Using the Alzheimer’s Disease Neuroimaging Initiative, a database that compiles data from nationwide studies, we analyze cognitive function (memory and visuospatial ability), plasma biomarkers (amyloid β 42/40 ratio), and brain imaging (hippocampal volume). Data analysis consists of using programs such as Python and JASP to analyze data from the ADNI database, and finding significant relationships between variables through statistical analysis. Our results suggest that the impact of the e4 allele on memory and visuospatial ability over time may be strong in people who show early cognitive decline, independent of age, sex and education, and that hippocampal volume loss is greater in people who carry the e4 allele independent of covariates. Furthermore, it is unclear if plasma biomarkers reflect brain pathology. Team BRAIN’s future research goals include addressing disparities in AD development among different demographic and socioeconomic groups, using our findings to work towards a novel and cost-effective approach to diagnosing and treating AD to eradicate boundaries in the access to care, applying machine learning to propose a model of prediction and longitudinal progression, and expanding the variable set to include more biomarkers

Bnip3 as a Dual Regulator of Mitochondrial Turnover and Cell Death in the Myocardium

The Bcl-2 adenovirus E1B 19 kDa-interacting protein 3 (Bnip3) is a pro-apoptotic BH3-only protein associated with the pathogenesis of many diseases, including cancer and cardiovascular disease. Studies over the past decade have provided insight into how Bnip3 induces mitochondrial dysfunction and subsequent cell death in cells. More recently, Bnip3 was identified as a potent inducer of autophagy in cells. However, the functional role of Bnip3-mediated autophagy has been difficult to define and remains controversial. New evidence has emerged suggesting that Bnip3 is an important regulator of mitochondrial turnover via autophagy in the myocardium. Also, studies suggest that the induction of Bnip3-dependent mitochondrial autophagy is a separately activated process independent of Bax/Bak and the mitochondrial permeability transition pore (mPTP). This review discusses the current understanding of the functional role that Bnip3 plays in the myocardium. Recent studies suggest that Bnip3 might have a dual function in the myocardium, where it regulates both mitochondrial turnover via autophagy and cell death and that these are two separate processes activated by Bnip3