Biology subjects

Tanzi, R.

Publications and source records attributed to Tanzi, R..

3 recordsLinked to original sources

bioRxiv2021

Reporting amyloid beta levels via bioluminescence imaging with amyloid reservoirs inAlzheimer's disease models

Bioluminescence imaging has changed daily practice in preclinical research of cancers and other diseases in the last decades; however, it has been rarely applied in preclinical research of Alzheimers disease (AD). In this report, we demonstrated that bioluminescence imaging could be used to report the levels of amyloid beta (A{beta}) species in vivo. We hypothesized that AkaLumine, a newly discovered substrate for luciferase, could bind to A{beta} aggregates and plaques. We further speculated that the A{beta} species have the reservoir capacity to sequester and release AkaLumine to control the bioluminescence intensity, which could be used to report the levels of A{beta}s. Our hypotheses have been validated via in vitro solution tests, mimic studies with brain tissues and mice, two-photon imaging with AD mice, and in vivo bioluminescence imaging using transgenic AD mice that were virally transduced with aka Luciferase (AkaLuc), a new luciferase that generates bioluminescence in the near infrared window. As expected, compared to the control group, we observed that the A{beta} group showed lower bioluminescence intensity due to AkaLumine sequestering at early time points, while higher intensity due to AkaLumine releasing at later time points. Lastly, we demonstrated that this method could be used to monitor AD progression and therapeutic effectiveness of avagacestat, a well-studied gamma-secretase inhibitor. Importantly, a good correlation (R2 = 0.81) was established between in vivo bioluminescence signals and A{beta} burdens of the tested AD mice. We believe that our approach can be easily implemented into daily imaging experiments and has tremendous potential to change daily practice of preclinical AD research.

neuroscience↗

bioRxiv2021

A smoothed version of the Lassosum penalty for fitting integrated risk models

Polygenic risk scores are a popular means to predict the disease risk or disease susceptibility of an individual based on its genotype information. When adding other important epidemiological covariates such as age or sex, we speak of an integrated risk model. Methodological advances for fitting more accurate integrated risk models are of immediate importance to improve the precision of risk prediction, thereby potentially identifying patients at high risk early on when they are still able to benefit from preventive steps/interventions targeted at increasing their odds of survival, or at reducing their chance of getting a disease in the first place. This article proposes a smoothed version of the "Lassosum" penalty used to fit polygenic risk scores and integrated risk models. The smoothing allows one to obtain explicit gradients everywhere for efficient minimization of the Lassosum objective function while guaranteeing bounds on the accuracy of the fit. An experimental section on both Alzheimers disease and COPD (chronic obstructive pulmonary disease) demonstrates the increased accuracy of the proposed smoothed Lassosum penalty compared to the original Lassosum algorithm, allowing it to draw equal with state-of-the-art methodology such as LDpred2 when evaluated via the AUC (area under the ROC curve) metric.

bioinformatics↗

bioRxiv2020

Non-invasive red-light optogenetic control of Drosophila cardiac function

Drosophila is a powerful genetic model system for cardiovascular studies. Recently, optogenetic pacing tools have been developed to control Drosophila heart rhythm noninvasively with blue light, which has a limited penetration depth. Here we developed both a red-light sensitive opsin expressing Drosophila system and an integrated red-light stimulation and optical coherence microscopy (OCM) imaging system. We demonstrated noninvasive control of Drosophila cardiac rhythms, including simulated tachycardia in ReaChR-expressing flies and bradycardia and cardiac arrest in halorhodopsin (NpHR)-expressing flies at multiple developmental stages. By using red excitation light, we were able to pace flies at higher efficiency and with lower power than with equivalent blue light excitation systems. The recovery dynamics after red-light stimulation of NpHR flies were observed and quantified. The combination of red-light stimulation, OCM imaging, and transgenic Drosophila systems provides a promising and easily manipulated research platform for noninvasive cardiac optogenetic studies.

bioengineering↗