Jagged1 Is Altered in Alzheimer's Disease and Regulates Spatial Memory Processing

Abstract

Notch signaling plays an instrumental role in hippocampus-dependent memory formation and recent evidence indicates a displacement of Notch1 and a reduction its activity in hippocampal and cortical neurons from Alzheimer's disease (AD) patients. As Notch activation depends on ligand availability, we investigated whether Jagged1 expression was altered in brain specimen of AD patients. We found that Jagged1 expression was reduced in the CA fields and that there was a gradual reduction of Jagged1 in the cerebrospinal fluid (CSF) with the progression of dementia. Given the role of Notch signaling in memory encoding, we investigated whether targeted loss of Jagged1 in neurons may be responsible for the memory loss seen in AD patients. Using a transgenic mouse model, we show that the targeted loss of Jagged1 expression during adulthood is sufficient to cause spatial memory loss and a reduction in exploration-dependent Notch activation. We also show that Jagged1 is selectively enriched at the presynaptic terminals in mice. Overall, the present data emphasizes the role of the Notch ligand, Jagged1, in memory formation and the potential deficit of the signaling ligand in AD patients.

Systematic Analysis of Gene Expression Profiles Controlled by hnRNP Q and hnRNP R, Two Closely Related Human RNA Binding Proteins Implicated in mRNA Processing Mechanisms

“…Furthermore, the maturation factor of NADPH oxidase Dual oxidase 1 (DUOXA1) was found to promote neuronal-like differentiation of p19 embryonal carcinoma cells following p53 expression (Ostrakhovitch and Semenikhin, 2011 ). Interestingly, JAG1 and, in a more general view, the Notch signaling pathway are important for the spatial memory and their expression is altered in the hippocampus of people suffering from Alzheimer's disease (Marathe et al, 2017 ). In addition, HMOX1 expression is also up-regulated in neurons and astrocytes derived from hippocampus, cerebral cortex, and subcortical white matter of Alzheimer's patients (Schipper et al, 1995 ).…”

Familial Alzheimer’s Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis

“…The importance for Notch-γ-secretase interactions is highlighted by the halting of γ-secretase inhibitor trials due to off-target effects on Notch signaling ( Doody et al., 2013 ). In support of the role of aberrant Notch signaling in AD, Notch proteins have been shown to be a component of amyloid plaques in postmortem tissue ( Brai et al., 2016 ) and the Notch ligand Jagged is reduced in AD ( Marathe et al., 2017 ). Further work is required to disentangle cell-autonomous versus non-cell-autonomous pathomechanisms of fAD mutations on neurogenesis.…”

MicroRNA-98 reduces amyloid β-protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer's disease mice

“…In the miR-98 inhibitor group, the expression of miR-98 was lower and the expression levels of HEY2, Jagged1, Notch1, Hes1, Hes5, APP and Bax were higher, whereas the expression of Bcl-2 was lower. Jagged1 is a Notch ligand; the targeted loss of this expression was shown to be sufficient to cause spatial memory loss and a reduction in the activation of exploration-dependent Notch ( 39 ). The Notch1 pathway is a cellular cascade with basic roles from brain development to adult brain function; the overactivation of Notch1 following brain injury is detrimental for neuronal survival ( 40 ).…”