Biology subjects

Ribeiro, F. C.

Publications and source records attributed to Ribeiro, F. C..

3 recordsLinked to original sources

bioRxiv2023

Stimulation of mRNA translation rescues hippocampal synaptic plasticity and memory in mouse models of Alzheimer's disease

Impaired synaptic plasticity and progressive memory deficits are major hallmarks of Alzheimers disease (AD). Hippocampal mRNA translation, required for memory consolidation, is defective in AD. Here, we show that systemic treatment with (2R,6R)- hydroxynorketamine (HNK), an active metabolite of the antidepressant ketamine, prevented deficits in hippocampal mRNA translation, long-term potentiation (LTP) and memory induced by AD-linked amyloid-{beta} oligomers (A{beta}Os) in mice. HNK activated hippocampal extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 (S6), which promote protein synthesis and synaptic plasticity. Stimulation of S6 phosphorylation by HNK was mTORC1-dependent, while rescue of hippocampal LTP and memory in HNK-treated A{beta}O-infused mice was ERK1/2-dependent and, partially, mTORC1- dependent. Remarkably, treatment with HNK corrected LTP and memory deficits in aged APP/PS1 mice. Transcriptomic analysis further showed that HNK rescued signaling pathways that are aberrant in APP/PS1 mice, including inflammatory and hormonal responses, and programmed cell death. Taken together, our findings demonstrate that HNK induces signaling and transcriptional responses that correct deficits in hippocampal synaptic plasticity and memory in AD mouse models. These results raise the prospect that HNK could serve as a therapeutic to prevent or reverse memory decline in AD.

neuroscience↗

bioRxiv2022

The unfolded protein response transcription factor XBP1s ameliorates Alzheimer`s disease by improving synaptic function and proteostasis

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimers disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). A polymorphism in the XBP1 promoter has been suggested as a risk factor for AD. To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in neurons using preclinical models. Overexpression of an active form of XBP1 in the nervous system using transgenic mice significantly reduced the load of amyloid deposits in the cerebral cortex and hippocampus and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved long-term potentiation, memory performance, and dendritic spine density. Quantitative proteomics of the hippocampus revealed that XBP1 expression corrects a large proportion of the alterations observed in the 5xFAD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

animal behavior and cognition↗

bioRxiv2021

Age-linked suppression of lipoxin A4 mediates cognitive deficits in mice and humans

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimers disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associates with memory performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.

neuroscience↗