Dataset Information

A proteomic study to unveil lead toxicity-induced memory impairments invoked by synaptic dysregulation.

ABSTRACT: Lead (Pb²⁺), a ubiquitously present heavy metal toxin, has various detrimental effects on memory and cognition. However, the molecular processes affected by Pb²⁺ causing structural and functional anomalies are still unclear. To explore this, we employed behavioral and proteomic approaches using rat pups exposed to lead acetate through maternal lactation from postnatal day 0 (P0) until weaning. Behavioral results from three-month-old rats clearly emphasized the early life Pb²⁺ exposure induced impairments in spatial cognition. Further, proteomic analysis of synaptosomal fractions revealed differential alteration of 289 proteins, which shows functional significance in elucidating Pb²⁺ induced physiological changes. Focusing on the association of Small Ubiquitin-like MOdifier (SUMO), a post-translational modification, with Pb²⁺ induced cognitive abnormalities, we identified 45 key SUMO target proteins. The significant downregulation of SUMO target proteins such as metabotropic glutamate receptor 3 (GRM3), glutamate receptor isoforms 2 and 3 (GRIA 2 and GRIA3) and flotilin-1 (FLOT1) indicates SUMOylation at the synapses could contribute to and drive Pb²⁺ induced physiological imbalance. These findings identify SUMOylation as a vital protein modifier with potential roles in hippocampal memory consolidation and regulation of cognition.

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The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD034212".

SUBMITTER: Mohanraj N

PROVIDER: S-EPMC9742914 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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A proteomic study to unveil lead toxicity-induced memory impairments invoked by synaptic dysregulation.

Mohanraj Nivedha N Joshi Neha S NS Poulose Roshni R Patil Rahul R RR Santhoshkumar Rashmi R Kumar Anubhav A Waghmare Girish P GP Saha Amit Kumar AK Haider Syeda Zehra SZ Markandeya Yogananda S YS Dey Gourav G Rao Laxmi T LT Govindaraj Periyasamy P Mehta Bhupesh B

Toxicology reports 20220707

Lead (Pb<sup>2+</sup>), a ubiquitously present heavy metal toxin, has various detrimental effects on memory and cognition. However, the molecular processes affected by Pb<sup>2+</sup> causing structural and functional anomalies are still unclear. To explore this, we employed behavioral and proteomic approaches using rat pups exposed to lead acetate through maternal lactation from postnatal day 0 (P0) until weaning. Behavioral results from three-month-old rats clearly emphasized the early life Pb ...[more]

PMID: 36518382

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Project description:BackgroundSynaptic dysfunction, characterized by synapse loss and structural alterations, emerges as a prominent correlate of cognitive decline in Alzheimer's disease (AD). Actin cytoskeleton, which serves as the structural backbone of synaptic architecture, is observed to be lost from synapses in AD. Actin cytoskeleton loss compromises synaptic integrity, affecting glutamatergic receptor levels, neurotransmission, and synaptic strength. Understanding these molecular changes is crucial for developing interventions targeting synaptic dysfunction, potentially mitigating cognitive decline in AD.MethodsIn this study, we investigated the synaptic actin interactome using mass spectrometry in a mouse model of AD, APP/PS1. Our objective was to explore how alterations in synaptic actin dynamics, particularly the interaction between PSD-95 and actin, contribute to synaptic and cognitive impairment in AD. To assess the impact of restoring F-actin levels on synaptic and cognitive functions in APP/PS1 mice, we administered F-actin stabilizing agent, jasplakinolide. Behavioral deficits in the mice were evaluated using the contextual fear conditioning paradigm. We utilized primary neuronal cultures to study the synaptic levels of AMPA and NMDA receptors and the dynamics of PSD-95 actin association. Furthermore, we analyzed postmortem brain tissue samples from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer's dementia (AD) to determine the association between PSD-95 and actin.ResultsWe found a significant reduction in PSD-95-actin association in synaptosomes from middle-aged APP/PS1 mice compared to wild-type (WT) mice. Treatment with jasplakinolide, an actin stabilizer, reversed deficits in memory recall, restored PSD-95-actin association, and increased synaptic F-actin levels in APP/PS1 mice. Additionally, actin stabilization led to elevated synaptic levels of AMPA and NMDA receptors, enhanced dendritic spine density, suggesting improved neurotransmission and synaptic strength in primary cortical neurons from APP/PS1 mice. Furthermore, analysis of postmortem human tissue with NCI, MCI and AD subjects revealed disrupted PSD-95-actin interactions, underscoring the clinical relevance of our preclinical studies.ConclusionOur study elucidates disrupted PSD-95 actin interactions across different models, highlighting potential therapeutic targets for AD. Stabilizing F-actin restores synaptic integrity and ameliorates cognitive deficits in APP/PS1 mice, suggesting that targeting synaptic actin regulation could be a promising therapeutic strategy to mitigate cognitive decline in AD.

Dataset Information

A proteomic study to unveil lead toxicity-induced memory impairments invoked by synaptic dysregulation.

Data availbility

Publications

A proteomic study to unveil lead toxicity-induced memory impairments invoked by synaptic dysregulation.

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