A multitude of signaling pathways associated with Alzheimer's disease and their roles in AD pathogenesis and therapy

Gadhave, Kundlik; Kumar, Deepak; Uversky, Vladimir N.; Giri, Rajanish

doi:10.1002/med.21719

Cited by 39 publications

(34 citation statements)

References 570 publications

(1,131 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…transcriptional and post-transcriptional regulation, influencing the biological repertoire of both neurons and glia. These adaptive changes are fundamental in supporting brain functions, such as learning and memory (Gomazkov, 2015), but can also propagate neuropathological signals contributing to progressive neurological deficits (Gadhave et al, 2020). NOTCH1 signaling, an evolutionarily conserved pathway fundamental for brain development and neural stem cell maintenance (Falo-Sanjuan and Bray, 2020), has been previously implicated in neural network function and demise.…”

Section: Introductionmentioning

confidence: 99%

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

Perna

Marathe

Dreos

et al. 2021

Molecular and Cellular Neuroscience

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

Perna

Marathe

Dreos

et al. 2021

Molecular and Cellular Neuroscience

View full text Add to dashboard Cite

show abstract

“…The complex pathophysiology observed in AD is associated with the accumulation of plaques and the formation of NFTs, along with other pathological changes, resulting in synaptic dysfunction, excitotoxicity, dendritic spine loss and overall destabilization of the neural network [ 6 , 7 ]. The overaccumulation of Aβ is considered as the prominent cause of disease severity and neuronal cell death; however, the precise mechanism of interconnecting AD onset and progression is not fully understood, despite the identification of signaling pathways that exert determinant roles [ 8 , 9 ]. One such crucial signaling molecule that may represent a critical determinant is collapse response mediator 2 (CRMP2).…”

Section: Introductionmentioning

confidence: 99%

Somatostatin Ameliorates β-Amyloid-Induced Cytotoxicity via the Regulation of CRMP2 Phosphorylation and Calcium Homeostasis in SH-SY5Y Cells

et al. 2021

View full text Add to dashboard Cite

Somatostatin is involved in the regulation of multiple signaling pathways and affords neuroprotection in response to neurotoxins. In the present study, we investigated the role of Somatostatin-14 (SST) in cell viability and the regulation of phosphorylation of Collapsin Response Mediator Protein 2 (CRMP2) (Ser522) via the blockade of Ca2+ accumulation, along with the inhibition of cyclin-dependent kinase 5 (CDK5) and Calpain activation in differentiated SH-SY5Y cells. Cell Viability and Caspase 3/7 assays suggest that the presence of SST ameliorates mitochondrial stability and cell survival pathways while augmenting pro-apoptotic pathways activated by Aβ. SST inhibits the phosphorylation of CRMP2 at Ser522 site, which is primarily activated by CDK5. Furthermore, SST effectively regulates Ca2+ influx in the presence of Aβ, directly affecting the activity of calpain in differentiated SH-SY5Y cells. We also demonstrated that SSTR2 mediates the protective effects of SST. In conclusion, our results highlight the regulatory role of SST in intracellular Ca2+ homeostasis. The neuroprotective role of SST via axonal regeneration and synaptic integrity is corroborated by regulating changes in CRMP2; however, SST-mediated changes in the blockade of Ca2+ influx, calpain expression, and toxicity did not correlate with CDK5 expression and p35/25 accumulation. To summarize, our findings suggest two independent mechanisms by which SST mediates neuroprotection and confirms the therapeutic implications of SST in AD as well as in other neurodegenerative diseases where the effective regulation of calcium homeostasis is required for a better prognosis.

show abstract

“…Signaling cascades respond to synaptic activity and contribute to network plasticity through transcriptional and post-transcriptional regulation, influencing the biological repertoire of both neurons and glia. These adaptive changes are fundamental in supporting brain functions, such as learning and memory [22], but can also propagate neuropathological signals contributing to progressive neurological deficits seen in Alzheimer's disease [23]. Notch1 signaling, an evolutionarily conserved pathway fundamental for brain development and neural stem cell maintenance [24], has been previously implicated in AD.…”

Section: Introductionmentioning

confidence: 99%

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

Perna

Marathe

Dreos

et al. 2021

Preprint

View full text Add to dashboard Cite

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.

show abstract

A multitude of signaling pathways associated with Alzheimer's disease and their roles in AD pathogenesis and therapy

Cited by 39 publications

References 570 publications

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

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

Somatostatin Ameliorates β-Amyloid-Induced Cytotoxicity via the Regulation of CRMP2 Phosphorylation and Calcium Homeostasis in SH-SY5Y Cells

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

Contact Info

Product

Resources

About