Revealing Notch-dependencies in synaptic targets associated with Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the major cause of dementia. There is evidence that synaptic dysfunction and perturbation of Excitatory/Inhibitory (E/I) balance arises at the early stages of AD, altering the normal neural network activity, and leading to cognitive decline. Recent studies have identified Notch signaling as a contributor to neurodegenerative advancement including AD pathophysiology. As part of the efforts to understand molecular mechanisms and players involved in cognitive decline, we employed transgenic mouse models with Notch1 and RBPJK loss of function (LOF) in pyramidal neurons of the CA fields. Using bulk RNAseq. We have investigated the differential expression of Notch-dependent genes either upon environmental enrichment (EE) or upon Kainate injury. We found a substantial genetic diversity in absence of both Notch1 receptor or Rbpjk transcriptional activator. Among differentially expressed genes, we observed a significant upregulation of Gabra2a in both knockout models, suggesting a role for Notch signaling in the modulation of E/I balance. Upon neuroexcitotoxic stimulation, loss of Rbpjk results in decreased expression of synaptic proteins with neuroprotective effects confirmed to be under direct (Nptx2, Npy, Pdch8, TncC) or indirect (Bdnf and Scg2) control of Notch1/Rbpjk. Finally, we translate these findings into the human entorhinal cortex from AD patients performing targeted transcripts analysis. We confirm an increased trend for Rbpjk and the ligand DNER but not Notch1 expression. On the other hand, neuron-specific targets, Nptx2, Npy, BDNF and Gabra2a are upregulated during the mild-moderate stage and decline in the severe phase of the disease. These findings identify Notch as as promising signaling to finetune in order to ameliorate synaptic transmission and memory deficits that occur during the early phase of Alzheimer's Disease.