Mass spectrometry analysis of tau and amyloid-beta in iPSC-derived models of Alzheimer's disease and dementia

Induced pluripotent stem cell (iPSC) technology enables the generation of human neurons in vitro, which contain the precise genome of the cell donor, therefore permitting the generation of disease models from individuals with a disease-associated genotype of interest. This approach has been extensively used to model inherited forms of Alzheimer's disease and frontotemporal dementia. The combination of iPSC-derived neuronal models with targeted mass spectrometry analysis has provided unprecedented insights into the regulation of specific proteins in human neuronal physiology and pathology. For example enabling investigations into tau and APP/Aβ, specifically: protein isoform expression, relative levels of cleavage fragments, aggregated species and functionally critical post-translational modifications. The use of mass spectrometry has enabled a determination of how closely iPSC-derived models recapitulate disease profiles observed in the human brain. This review will highlight the progress to date in studies using iPSCs and mass spectrometry to model Alzheimer's disease and dementia. We go on to convey our optimism, as studies in the near future will make use of this precedent, together with novel techniques such as genome editing and stable isotope labelling, to provide real progress towards an in depth understanding of early neurodegenerative processes and development of novel therapeutic agents

Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis

Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of γ-secretase, cause familial Alzheimer’s disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and γ-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease

Multi-Temporal InSAR Analysis for Monitoring Ground Deformation in Amorgos Island, Greece

Radar Interferometry is a widely used method for estimating ground deformation, as it provides precision to a few millimeters to centimeters, and at the same time, a wide spatial coverage of the study area. On 9 July 1956, one of the strongest earthquakes of the 20th century in the area of the South Aegean, occurred in Amorgos, with a magnitude of Mw = 7.7. The objective of this research is to map ground deformation in Amorgos island, using InSAR techniques. We conducted a multi-temporal analysis of all available data from 2003 to 2019 by exploiting historical ENVISAT SAR imagery, as well as the dense archive of Sentinel-1 SLC imagery. Persistent Scatterer Interferometry (PS) and Small Baseline Subset (SBAS) methods were implemented. Results of both data-sets indicate a small-scale deformation on the island. A multi-track analysis was implemented on Sentinel-1 data to decompose the line of sight velocities to vertical and horizontal. The central south coast is experiencing horizontal movement, while uplift of a maximum value of 5 mm/y is observed in the southeastern coast. The combination of the good spatial coverage achievable via InSAR, with GPS measurements, is suggested an important tool for the seamless monitoring of Amorgos island towards tectonic hazard estimation

Primary portal vein hypoplasia with portal hypertension in a young dog

A 5-month old Caucasian dog was presented with a 20-day history of abdominal distention along with inappetance, depression and vomiting of 24-hour duration. Physical examination findings included depression, ascites, mild inspiratory dyspnea and dehydration. Clinicopathological evaluation revealed hyperammonemia, hypoalbuminemia, hyperbilirubinemia, hypoglycemia and hyponatremia. Microhepatia and free abdominal fluid was detected with abdominal ultrasonography. During exploratory laparotomy, multiple acquired portosystemic collateral vessels were found, indicative of portal hypertension, along with a small liver of normal color and texture. Liver histopathology included features consistent with liver hypoperfusion. These findings supported the diagnosis of primary portal vein hypoplasia with portal hypertension. The animal recovered uneventfully postoperatively and was discharged with diuretics, hepatoprotectants and a low-protein diet and remains healthy two years after diagnosis. This case underscores that a favorable prognosis may be anticipated in cases of primary portal vein hypoplasia with portal hypertension, thus, justifying the long-term conservative management instead of considering euthanasia