Biology subjects

Alberi, L.

Publications and source records attributed to Alberi, L..

2 recordsLinked to original sources

bioRxiv2021

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

Alzheimers 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 arise 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 of 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 (KA). 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. 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 Alzheimers Disease patients performing targeted transcripts analysis. We observe 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 a promising signaling cascade to fine-tune in order to ameliorate synaptic transmission and memory deficits that occur during early phase of the Alzheimers Disease. HighlightsO_LILoss of canonical and/or non-canonical Notch1 signaling in pyramidal neurons of the hippocampal CA field mainly affects the post-synaptic compartment. C_LIO_LIIn both RBPJKcKO and Notch1cKO mouse models there is upregulation of GABAergic receptor subunit alpha2 (Gabra2a). C_LIO_LIThe plasticity genes: Npy, Nptx2,Pcdh8 and TncC with neuroprotective functions and known association with Alzheimers Disease are direct Notch/Rbpjk targets. C_LIO_LIDuring the mild-moderate stage of AD dementia, Notch canonical signaling promotes the expression of neuroprotective proteins, in the attempt of mitigating the effect of the excitatory-inhibitory imbalance. This activity is not observed during severe stages of the disease. C_LI

neuroscience↗

bioRxiv2020

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology.

BackgroundAlzheimers disease (AD) is the primary cause of cognitive deficit in elderly humans. Late-onset AD (LOAD) is sporadic, multifactorial, non-Mendelian accounting at present for 95% of the cases in contrast to the genetic form. Risk factors for sporadic AD include Gene: Environment interactions. There is increasing evidence that lifestyle and environmental stress such as infection and chronic inflammation are underlying culprits of neurodegenerative dementia. Dementias that share or mimic pathological processes of AD include cerebrovascular diseases, Lewy body disease, TDP-43 proteinopathy. To date, very few mouse models reproduce the pathophysiological progression of mixed-vascular-AD, while the majority of studies have employed transgenic animals reproducing the familial form. MethodsWe have re-engineered the Polyinosinic:polycytidylic acid (PolyI:C) sterile infection model in wildtype C57Bl6 mice to obtain chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months and 16 months), taking the hippocampus as a reference brain region, based on its vulnerability, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD and Controls (CTL), parallely in Vascular dementia (VaD) patient specimens. ResultsWe found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological rearrangements progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression over the course of aging, with a peak in differential expression at 9 months. We confirm that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD and VaD shows a reproducibility of some gene targets in vascular dementia specimens rather than AD ones, in which only GFAP is strongly increased at the severe stages. ConclusionsThe PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation is sufficient to cause neuropathological processes resembling a mixed-VaD-AD phenotype, with progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling and the loss of neuronal functionality seen to some extent in humans.

neuroscience↗