Revealing NOTCH-dependencies in synaptic targets associated with Alzheimer's disease

Abstract

Recent studies have identified NOTCH signaling as a contributor of neurodegeneration including Alzheimer's disease' (AD) pathophysiology. As part of the efforts to understand molecular mechanisms and players involved in neurodegenerative dementia, we employed transgenic mouse models with Notch1 and Rbpjk loss of function (LOF) mutation in pyramidal neurons of the CA fields. Using RNA-seq, we have investigated the differential expression of NOTCH-dependent genes either upon environmental enrichment (EE) or upon kainic acid (KA) 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 excitotoxic stimulation, loss of RBPJK results in decreased expression of synaptic proteins with neuroprotective effects. We confirmed Nptx2, Npy, Pdch8, TncC as direct NOTCH1/RBPJK targets and Bdnf and Scg2 as indirect targets. Finally, we translate these findings into human entorhinal cortex containing the hippocampal region from AD patients performing targeted transcripts analysis. We observe an increased trend for RBPJK and the ligand DNER starting in the mild-moderate stage of the disease with no change of NOTCH1 expression. Alongside, expression of the Notch targets Hes5 and Hey1 tend to rise in the intermediate stage of the disease and drop in severe AD. Similarly the newly discovered NOTCH targets, NPTX2, NPY, BDNF show an up-warding tendency during the mild-moderate stage, and decline in the severe phase of the disease. This study identifies NOTCH as a central signaling cascade capable of modulating synaptic transmission in response to excitatory insult through the activation of neuroprotective genes that have been associated to AD.

ESR1 dysfunction triggers neuroinflammation as a critical upstream causative factor of the Alzheimer’s disease process

“…Understanding the molecular cascade related to Notch activation during AD progression may elucidate the complicated signaling network that contributes to the progression of AD. Other studies have found that neural excitotoxicity also upregulates Notch signaling components and thus the severity of AD, which supports the possibility of Notch signaling involvement in postexcitotoxic neuronal demise [37]. Classically, microglial activation induces the expression of toll-like receptor (TLR) and triggers NF-kB-dependent inflammation, and subsequently upregulates inflammatory pathways through cytokines such as IL6, IL12, TNFα, and IL23 [38].…”

Construction and validation of a bioinformatics-based screen for Cuproptosis-related genes and risk model for Alzheimer's disease

“…The difference between Cluster 1 and Cluster 2 in the marker pathway activity also revealed a signi cant increase in Notch signaling pathway activity. Arunima Kapoor et al and Perna et al also reported a relationship between this signaling pathway and AD [49,50].…”

Histone H3 Lysine 4 and 27 Trimethylation Landscape of Human Alzheimer’s Disease

“…H3K4me3 and H3K27me3 ChIP-seq data were generated using postmortem entorhinal cortex tissues collected from 15 elderly individuals, as previously described by Bathini et al [ 13 ] and Perna et al [ 14 ] (mean age = 76.2, s.d. = 7.75, range = 61–86, mean postmortem delay = ~41 h, s.d = ~21 h), comprising both AD cases ( n = 6, mean Braak stage = 5.66, s.d.…”

“…Frozen human entorhinal cortex ( n = 15) tissues were generously provided by the Medical Research Council Brain Bank for Dementia Research, Oxford (UK), and have previously been described by Bathini et al [ 13 ] and Perna et al [ 14 ]. The use of human tissues has been approved by the Ethical Commission of the Brain Bank for Dementia UK (OBB443 registered 1 May 2017 and OB344 registered 1 February 2017).…”