Past events

With our rapidly aging population, Alzheimer’s disease (AD) is often considered the plague of the 21st century. While much is known regarding the direct genetic mutations that trigger the rare familial form of the disease (FAD), molecular mechanisms driving the emergence of late-onset sporadic AD (SAD) remain elusive. A distinctively human predicament, AD is a protein-based disease characterized by toxic protein build up in the brain. The principal mechanisms for protein turnover or removal are dependent on ubiquitin. We will describe evidence that interference with ubiquitin signalling in a 3-dimentional human neuronal culture is sufficient to cause the two pathological hallmarks of AD (A plaques and neurofibrillary tangles), even in the absence of any familial mutations. By utilizing this platform, we specifically demonstrate that attenuated ubiquitin-dependent turnover leads to elevated levels of the Amyloid Precursor Protein (APP), enhanced secretion of the toxic amyloid-β42 peptide, and extra-cellular amyloid plaque build-up. Furthermore, we demonstrate that impaired ubiquitin signalling is a common feature of different human and murine models of AD, whereas overcoming this impairment is sufficient to decrease formation of A plaques and neurofibrillary tangles in an experimental model of FAD. To summarise, our work uncovers a role for ubiquitin during the early “cellular phase” of neurodegeneration that underlies emergence and progression of AD, providing hope that tweaking components of the ubiquitin-proteasome system has the potential to decrease risk for developing AD pathology, opening up new therapeutic approaches.

Primates live in large and complex social groups. It has been argued that this has led to evolutionary pressure on the brain and that there are networks that have been evolved to play an important role in social cognition and behaviors. Social deficits are widely known in many brain disorders such as autism and anxiety. Here we focused on two brain areas that were shown to play a crucial role in social interactions – the amygdala and the anterior-cingulate-cortex (ACC). Our goal was to understand the neural codes in these two regions and especially under social interactions: 1. Computational techniques that allow the comparison of on-going neural activity across these brain regions and species based on information theory measures was developed. We found that human neurons better utilize information capacity (efficient coding) than macaque neurons in both regions, and that ACC neurons are more efficient than amygdala neurons, in both species. In contrast, we found more overlap in the neural vocabulary and more synchronized activity (robustness coding) in monkeys in both regions, and in the amygdala of both species. Our findings demonstrate a tradeoff between robustness and efficiency across species and regions. We suggest that this tradeoff can contribute to the differential cognitive functions between species, and can underlie the complementary roles of the amygdala and the ACC. It can also contribute to the fragility underlying human psychopathologies. For more, see https://www.sciencedirect.com/science/article/pii/S0092867418316465 2. A novel electrophysiology experiment that induced real and live social interactions between humans and primates was conducted. In each daily session, we recorded neural responses in monkeys to the eye-gaze, direct or averted, of human intruders, and compared it with the responses to valence conditioning, aversive and appetitive. We found that the primate amygdala, but not the ACC, encodes eye-gaze; this coding is shared with valence coding through two mechanisms – “shared-activity” at the expectation epoch (conditioned stimulus, CS) and “shared-intensity” after the outcome (unconditioned stimulus, US). These shared mechanisms can open an indirect window for future therapy. For more, see https://www.biorxiv.org/content/10.1101/736462v1 3. We developed behavioral methods and algorithms to evaluate primates’ emotional states, using the analysis of facial expressions and a number of physiological parameters such as heart rate and respiratory rate. The primates’ emotional state evaluation will be the substrate for future studies that will investigate the neural correlates of these states.