Yeast as a Model for Studying Aβ Aggregation, Toxicity and Clearance

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system, characterised by acute memory loss and behavioural symptoms. The AD brain is characterized by the presence of senile amyloid plaques associated with degenerating neurites and inflammatory processes. The major protein component of these amyloid deposits is the amyloid beta (Aβ) protein. The Aβ protein is a 40 or 42 amino acid cleavage product of APP (Amyloid Precursor Protein) which is produced in low levels in the normal ageing brain. Although senile amyloid plaques is the major pathological hallmark of AD brains, accumulating evidence has been presented to show that increased levels of soluble forms of Aβ42 correlate with the clinical manifestations and severity of the disease. Increased accumulation (both intracellular and extracellular) and toxicity of Aβ42 peptide in the brain play pivotal roles in neurodegeneration and loss of memory functions in the AD brain. Therefore reducing the toxicity of Aβ42 and increasing its clearance from the brain has been considered to be main targets for AD therapeutics. The search for a disease modifying therapy for AD has been very difficult with the majority of agents failing in later stages of clinical trials. The incomplete understanding of drug-target mechanisms and the lack of high-throughput screening systems for identifying selective target based drugs have been some of the main issues expressed for the failure of AD drugs. Yeast offer a simple eukaryotic model for studying pathological mechanisms and compared to other models there is availability of various experimental tools applicable for high throughput analysis of protein-protein, gene-gene and gene-protein interactions and associated cellular functions. It can also offer a versatile model for initial screening in drug development for various human diseases, including AD. Yeast models have been utilised for studying AD related proteins including APP and its processing enzymes (secretases) and tau phosphorylation

PRKAG2 gene expression is elevated and its protein levels are associated with increased amyloid-β accumulation in the Alzheimer’s Disease brain

Increased amyloid-β (Aβ) accumulation associated with abnormal autophagy-lysosomal activity and nutrient kinase dysregulation are common features in Alzheimer’s disease (AD) brain. Recent studies have identified PRKAG2 and TIPRL genes that control nutrient kinase regulated autophagy, and here we determined if their expression is altered in postmortem AD brains. Gene and protein expression of TIPRL were unchanged. However, gene expression of PRKAG2 was increased 3-fold and its protein levels positively correlated with Aβ accumulation in the AD brain. In summary, our findings suggest that increased PRKAG2 is an important contributing factor to Aβ accumulation in the AD brain

A rapid absorbance-based growth assay to screen the toxicity of oligomer Aβ42 and protect against cell death in yeast

Multiple lines of evidence show that soluble oligomer forms of amyloid β protein (Aβ42) are the most neurotoxic species in the brain and correlates with the degree of neuronal loss and cognitive deficit in Alzheimer\u27s disease. Although many studies have used mammalian cells to investigate oligomer Aβ42 toxicity, the use of more simple eukaryotic cellular systems offers advantages for large-scale screening studies. We have previously established and validated budding yeast, Saccharomyces cerevisiae to be a simple and a robust model to study the toxicity of Aβ. Using colony counting based methods, oligomeric Aβ42 was shown to induce dose-dependent cell death in yeast. We have adapted this method for high throughput screening by developing an absorbance-based growth assay. We further validated the assay with treatments previously shown to protect oligomer Aβ42 induced cell death in mammalian and yeast cells. This assay offers a platform for studying underlying mechanisms of oligomer Aβ42 induced cell death using gene deletion/overexpression libraries and developing novel agents that alleviate Aβ42 induced cell death. © 2020 Neural Regeneration Research. All rights reserved

Finding chemopreventatives to reduce amyloid beta in yeast

[No abstract available

Changes in the Characteristics of American Youth: Implications for Adult Outcomes

We examine changes in the characteristics of American youth between the late 1970s and the late 1990s, with a focus on characteristics that matter for labor market success. We reweight the NLSY79 to look like the NLSY97 along a number of dimensions that are related to labor market success, including race, gender, parental background, education, test scores, and variables that capture whether individuals transition smoothly from school to work. We then use the re-weighted sample to examine how changes in the distribution of observable skills affect employment and wages. We also use more standard regression methods to assess the labor market consequences of differences between the two cohorts. Overall, we find that the current generation is more skilled than the previous one. Blacks and Hispanics have gained relative to whites and women have gained relative to men. However, skill differences within groups have increased considerably and in aggregate the skill distribution has widened. Changes in parental education seem to generate many of the observed changes

Partition, migration, and jute cultivation in India

Climate change is expected to displace millions of involuntary migrants in Bangladesh. We draw on history to show that these ``environmental refugees'' can play a positive role in the regions that receive them by looking at the partition of India. We use an instrumental variables (IV) strategy to show that the migrants played a major role in India's take-up of jute cultivation. Our estimates suggest that migrants fully explain post-Partition jute cultivation. Consistent with migrants bringing jute-specific skills with them, we find that migrants increased jute yields and did not increase the cultivation of other crops

Partition, migration, and jute cultivation in India

We show that refugees can play positive roles in receiving economies by looking at the partition of India. We use an instrumental variables (IV) strategy to show that migrants played a major part in India's take-up of jute cultivation. Our estimates suggest that migrants fully explain post-partition jute cultivation. Consistent with migrants bringing jute-specific skills with them, we find that migrants did not depress jute yields, did not increase the cultivation of other crops, and did not lower native wages. Our results are robust to migrant selection into districts with the best markets for jute

The green revolution and infant mortality in India

We use a difference in differences approach to show that the adoption of High Yielding Varieties (HYV) reduced infant mortality in India. This holds even comparing children of the same mother. Children of mothers whose characteristics predict higher child mortality, rural children, boys, and low-caste children benefit more from HYV adoption. We find no obvious evidence that parental investments respond to HYV adoption. We find little evidence of selection into child bearing in response to HYV adoption

Characterisation of the structure and oligomerisation of islet amyloid polypeptides (IAPP): A review of molecular dynamics simulation studies

Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein whose abnormal aggregation into amyloid fibrils is a pathological feature in type 2 diabetes, and its cross-aggregation with amyloid beta has been linked to an increased risk of Alzheimer’s disease. The soluble, oligomeric forms of hIAPP are the most toxic to ß-cells in the pancreas. However, the structure of these oligomeric forms is difficult to characterise because of their intrinsic disorder and their tendency to rapidly aggregate into insoluble fibrils. Experimental studies of hIAPP have generally used non-physiological conditions to prevent aggregation, and they have been unable to describe its soluble monomeric and oligomeric structure at physiological conditions. Molecular dynamics (MD) simulations offer an alternative for the detailed characterisation of the monomeric structure of hIAPP and its aggregation in aqueous solution. This paper reviews the knowledge that has been gained by the use of MD simulations, and its relationship to experimental data for both hIAPP and rat IAPP. In particular, the influence of the choice of force field and water models, the choice of initial structure, and the configurational sampling method used, are discussed in detail. Characterisation of the solution structure of hIAPP and its mechanism of oligomerisation is important to understanding its cellular toxicity and its role in disease states, and may ultimately offer new opportunities for therapeutic interventions

Displacement and development: Long term impacts of population transfer in India

The partition of British India in 1947 resulted in one of the largest and most rapid migrations and population transfers of the 20th century. Using refugee presence by 1951 as a measure for the intensity of the impact of the population transfer, and district level data on agricultural output between 1911 and 2009 from India, we find using difference in differences and event study approaches that areas that received more refugees have higher average yields, are more likely to take up high yielding varieties of seeds, and are more likely to use agricultural technologies. The increase in yields and use of agricultural technology coincide with the timing of the Green Revolution in India. Using pre-partition data, we show that refugee placement is uncorrelated with soil and water table characteristics, agricultural infrastructure, and agricultural yields prior to 1947; hence, the effects are not explained by selective movement into districts with a higher potential for agricultural development. We highlight refugee literacy and land reforms in areas with refugees as two of the many potential mechanisms that could be driving these effects