Nutrient signaling pathways regulate amyloid clearance and synaptic loss in Alzheimer’s disease

Abstract

Extra-cellular accumulation of Amyloid-β (Aβ) plaques is causatively associated with Alzheimer's disease (AD). However, mechanisms that mediate the pre-pathological state of amyloid plaque formation remain elusive. Here, using paired RNAi and kinase inhibitor screens, we discovered that AKT-mediated insulin/nutrient signaling suppresses lysosomal clearance of Aβ and promotes amyloid formation. This mechanism is cell-autonomous and functions in multiple systems, including iPSC-derived human neurons and in vivo. Nutrient signaling regulates amyloid formation via distinct lysosomal functional mechanisms, while enhanced amino acid signaling promotes amyloid formation by transcriptionally suppressing lysosome biogenesis, and high intracellular cholesterol levels suppress lysosomal clearance of amyloid by increasing the number of non-functional lysosomes. The nutrient signaling pathway, present in both neurons and microglia, regulates lysosomal clearance of amyloid and microglia mediated synapse loss, both in vitro and in vivo. Clinically, older hyperlipidemic patients showed less synapse loss through microglia and performed better in cognitive tests. Thus, our results reveal a bi-partite cellular quality control system regulated by the insulin-nutrient signaling that in neurons regulates Aβ peptide clearance and in microglia regulates synaptic loss, both processes causally associated with AD. Our results also caution against reducing amyloid through such processes as this might also result in synapse loss.

Olanzapine, Risperidone and Clozapine prescribing is associated with increased risk for Alzheimer’s Disease reflecting antipsychotic-specific effects on microglial phagocytosis

“…To begin to understand the cause of this association, we sought to explore the cellular processes that may underpin our epidemiological findings. Specifically, we investigated the acute effects of these antipsychotics on Aβ production and clearance, and lysosomal levels using methods previouslty reported by our group ( Mondal et al, 2020 ). Neither Olanzapine nor Risperidone altered Aβ secretion in human iPSC-derived cortical neurons, but reduced microglial Aβ uptake, which was positively correlated with microglia LysoTracker Red levels.…”

Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics

“…Moreover, the depletion of TAR DNA-binding protein of 43 kDa, a protein that regulates cellular and whole-body metabolism, was shown to increase Aβ clearance by microglia accompanied with enhanced synaptic pruning both in vitro and in vivo [ 17 ]. Furthermore, starvation or inhibition of the insulin/insulin-like growth factor 1 nutrient signalling pathway in the microglia similarly increases phagocytosis of Aβ [ 18 ]. These studies provide intriguing evidence that microglial phagocytic activity can be controlled by targeting their metabolism and highlight the potential of metabolic manipulations to refine the protective role of microglia in AD and potentially other NDDs.…”