Biology subjects

Tolwinski, N.

Publications and source records attributed to Tolwinski, N..

3 recordsLinked to original sources

bioRxiv2023

Evaluating the transmission risk of amyloid beta peptide via ingestion

BackgroundRecent reports suggest that amyloid beta (A{beta}) peptides can exhibit prion-like pathogenic properties. Transmission of A{beta} peptide and the development of associated pathologies after surgeries with contaminated instruments and intravenous or intracerebral inoculations have now been reported across fish, rodents, primates, and humans. This raises a worrying prospect of A{beta} peptides also having other characteristics typical of prions, such as evasion of the digestive process. We asked if such transmission of A{beta} aggregates via ingestion was possible. MethodsWe made use of a transgenic Drosophila melanogaster line expressing human A{beta} peptide prone to aggregation. Fly larvae were fed to adult zebrafish under two feeding schemes. The first was a short-term, high-intensity scheme over 48 hours to determine transmission and retention in the gut. The second, long-term scheme specifically examined retention and accumulation in the brain. The gut and brain tissues were examined by histology, western blotting, and mass spectrometric analyses. ResultsNone of the analyses could detect A{beta} aggregates in the guts of zebrafish following ingestion, despite being easily detectable in the feed. Additionally, there was no detectable accumulation of A{beta} in the brain tissue or development of associated pathologies after prolonged feeding. ConclusionsWhile human A{beta} aggregates do not appear to be readily transmissible by ingestion across species, two prospects remain open. First, this mode of transmission, if occurring, may stay below a detectable threshold and may take much longer to manifest. A second possibility is that the human A{beta} peptide may not be able to trigger self-propagation or aggregation in other species. Either possibility requires further investigation, taking into account the possibility of such transmission from agricultural species used in the food industry.

neuroscience↗

bioRxiv2019

Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing neuronal human amyloid-β

Alzheimers disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (A{beta})-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human A{beta} peptide specifically in neurons (GRU102). Here, we focus on a deeper analysis of these metabolic changes associated with A{beta}-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics, biochemical studies and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level A{beta} expression. In particular, GRU102 show reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects are associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurs before any significant increase in global protein aggregate is detectable. Treatment with an antidiabetes drug, Metformin, reverses A{beta}-induced metabolic defects, reduces protein aggregation and normalizes the lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in AD pathology and a promising target for intervention.

neuroscience↗

bioRxiv2017

TGH: Trans-Generational Hormesis And The Inheritance Of Aging Resistance

Animals respond to dietary changes by adapting their metabolism to available nutrients through insulin and insulin-like growth factor signalling. Restricting calorie intake generally extends life and health span, but Drosophila fed non-ideal sugars such as galactose are stressed and have shorter life spans. Here, we report that although these flies have shorter life spans, their offspring show significant life extension if switched to a normal sugar (glucose) diet. We define this as TGH or trans-generational hormesis, a beneficial effect that comes from a mild stress. We trace the effects to changes in stress responses in parents, ROS production, effects on lipid metabolism, and changes in chromatin and gene expression. We find that this mechanism is similar to what happens to the long lived Indy mutants on normal food, but surprisingly find that Indy is required for life span extension for galactose fed flies. Indy mutant flies grown on galactose do not live longer as do their siblings grown on glucose, rather overexpression of Indy rescues lifespan for galactose reared flies. We define a process where sugar metabolism can generate epigenetic changes that are inherited by offspring, providing a mechanism for how transgenerational nutrient sensitivities are passed on.

biochemistry↗