Title: Metabolic control of amyloid f
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. We focus on achieving two main goals 1) To study how aging affects neurodegeneration – a) to continue my work on Alzheimer’s disease and b) to collaborate with the colleagues on FTD/ALS to study the commonality and distinguishing features of these neurodegenerative diseases. 2) To find an effective cure for Alzheimer’s disease What makes aging a cause of a loss in many biological capacities, including synaptic activity? This is the central question that I would be interested in addressing in the next coming years, particularly in the context of neurodegeneration. Many neurodegenerative diseases have aging as the main risk factor, suggesting that aging-dependent mechanisms influence the disease processes. Aging is a complex process dictated by metabolic dysregulation at a systems level. Not only our anabolic metabolism “slows” down but also aging-specific pathways are upregulated, which involve mostly pathways that are of catabolic nature. On top of this, nutrient intake is reduced, called the anorexia of aging and there is also an imbalance in hormonal control of appetite and nutrient assimilation setting what one calls as “frailty during aging”. Thus, during aging, there seems to be an imbalance that is skewed towards more catabolism where both the infrastructure as well as functionality of the system start to disintegrate. Neuroinflammation and microglial activation play crucial roles not only in the formation of the amyloid proteins relevant for many of these neurodegenerative diseases, but also in synaptic activity and synapse loss. We recently discovered that anabolic nutrient signalling, in neurons, inhibited lysosomal clearance and thus promoted amyloid accumulation. We also showed that inhibition of this signalling pathway in neurons, on the contrary, enhanced lysosomal clearance and reduced amyloid levels (Mondal, Bali et al, in revision). However, when this pathway was manipulated in microglia, the phagocytic cells of the brain, we saw that they not only displayed enhanced phagocytic activity and lysosomal amyloid clearance, but they also “indiscriminately” pruned synapses (Paolicelli et al, Neuron, 2017, 2017). While on one hand the enhanced phagocytic activity due to reduced nutrient signalling could clear the unwanted amyloid proteins, the fact that this also reduces synapses is of concern. In the late-stages in aging, insulin resistance could contribute to higher catabolic activity in both neurons and microglia that can create synaptic/neuronal atrophy, which further contributes to cognitive impairment. Based on this, I propose a new model termed the “Biphasic amyloid-synapse model for Alzheimer’s disease” (hypothesis paper submitted soon). Extending this model, it is luring to speculate that AD has a long disease phase where the actual cognition-affecting synaptopenia is preceded by an amyloid phase that can take years whereas in other diseases such as ALS/FTD the synaptopenia is reached fairly quickly. On the social side, I am interested in the democratisation of science through digital innovation - I am also the founder of ScienceMatters - the open access publishing platform for and Eureka - the blockchain based science review and rating platform - through which we hope to make science more open and honest


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL