Dataset Information

Early Changes in Transcriptomic Profiles in Synaptodendrosomes Reveal Aberrant Synaptic Functions in Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by the progressive decline of cognitive functions, and is closely associated with the dysfunction of synapses, which comprise the basic structure that mediates the communication between neurons. Although the protein architecture and machinery for protein translation at synapses are extensively studied, the impact that local changes in the mRNA reservoir have on AD progression is largely unknown. Here, we investigated the changes in transcriptomic profiles in the synaptodendrosomes purified from the cortices of AD mice at ages 3 and 6 months, a stage when early signatures of synaptic dysfunction are revealed. The transcriptomic profiles of synaptodendrosomes showed a greater number of localized differentially expressed genes (DEGs) in 6-month-old AD mice compared with mice 3 months of age. Gene Ontology (GO) analysis showed that these DEGs are majorly enriched in mitochondrial biogenesis and metabolic activity. More specifically, we further identified three representative DEGs in mitochondrial and metabolic pathways-Prnp, Cst3, and Cox6c-that regulate the dendritic spine density and morphology in neurons. Taken together, this study provides insights into the transcriptomic changes in synaptodendrosomes during AD progression, which may facilitate the development of intervention strategies targeting local translation to ameliorate the pathological progression of AD.

SUBMITTER: Qu X

PROVIDER: S-EPMC9408306 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Early Changes in Transcriptomic Profiles in Synaptodendrosomes Reveal Aberrant Synaptic Functions in Alzheimer's Disease.

Qu Xueqi X Lin Li L Yi Wanying W Sun Changyu C Chen Yuewen Y Chen Yu Y

International journal of molecular sciences 20220810 16

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by the progressive decline of cognitive functions, and is closely associated with the dysfunction of synapses, which comprise the basic structure that mediates the communication between neurons. Although the protein architecture and machinery for protein translation at synapses are extensively studied, the impact that local changes in the mRNA reservoir have on AD progression is largely unknown. Here, ...[more]

PMID: 36012153

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Project description:Cows can live for over 20 years, but their productive lifespan averages only around 3 years after first calving. Liver dysfunction can reduce lifespan by increasing the risk of metabolic and infectious disease. This study investigated the changes in hepatic global transcriptomic profiles in early lactation Holstein cows in different lactations. Cows from five herds were grouped as primiparous (lactation number 1, PP, 534.7 ± 6.9 kg, n = 41), or multiparous with lactation numbers 2-3 (MP2-3, 634.5 ± 7.5 kg, n = 87) or 4-7 (MP4-7, 686.6 ± 11.4 kg, n = 40). Liver biopsies were collected at around 14 days after calving for RNA sequencing. Blood metabolites and milk yields were measured, and energy balance was calculated. There were extensive differences in hepatic gene expression between MP and PP cows, with 568 differentially expressed genes (DEGs) between MP2-3 and PP cows, and 719 DEGs between MP4-7 and PP cows, with downregulated DEGs predominating in MP cows. The differences between the two age groups of MP cows were moderate (82 DEGs). The gene expression differences suggested that MP cows had reduced immune functions compared with the PP cows. MP cows had increased gluconeogenesis but also evidence of impaired liver functionality. The MP cows had dysregulated protein synthesis and glycerophospholipid metabolism, and impaired genome and RNA stability and nutrient transport (22 differentially expressed solute carrier transporters). The genes associated with cell cycle arrest, apoptosis, and the production of antimicrobial peptides were upregulated. More surprisingly, evidence of hepatic inflammation leading to fibrosis was present in the primiparous cows as they started their first lactation. This study has therefore shown that the ageing process in the livers of dairy cows is accelerated by successive lactations and increasing milk yields. This was associated with evidence of metabolic and immune disorders together with hepatic dysfunction. These problems are likely to increase involuntary culling, thus reducing the average longevity in dairy herds.

Project description:The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function. With regard to the latter, the recent disappointing series of failed Phase III clinical trials targeting Aβ and APP processing, in concert with poor association between brain Aβ levels and cognitive function, have led many to call for a re-evaluation of the primacy of the amyloid cascade hypothesis. In this review, we integrate new insights into one of the earliest described signaling abnormalities in AD pathogenesis, namely intracellular Ca2+ signaling disruptions, and focus on its role in driving synaptic deficits - which is the feature that does correlate with AD-associated memory loss. Excess Ca2+release from intracellular stores such as the endoplasmic reticulum (ER) has been well-described in cellular and animal models of AD, as well as human patients, and here we expand upon recent developments in ER-localized release channels such as the IP3R and RyR, and the recent emphasis on RyR2. Consistent with ER Ca2+ mishandling in AD are recent findings implicating aspects of SOCE, such as STIM2 function, and TRPC3 and TRPC6 levels. Other Ca2+-regulated organelles important in signaling and protein handling are brought into the discussion, with new perspectives on lysosomal regulation. These early signaling abnormalities are discussed in the context of synaptic pathophysiology and disruptions in synaptic plasticity with a particular emphasis on short-term plasticity deficits. Overall, we aim to update and expand the list of early neuronal signaling abnormalities implicated in AD pathogenesis, identify specific channels and organelles involved, and link these to proximal synaptic impairments driving the memory loss in AD. This is all within the broader goal of identifying novel therapeutic targets to preserve cognitive function in AD.

Dataset Information

Early Changes in Transcriptomic Profiles in Synaptodendrosomes Reveal Aberrant Synaptic Functions in Alzheimer's Disease.

Publications

Early Changes in Transcriptomic Profiles in Synaptodendrosomes Reveal Aberrant Synaptic Functions in Alzheimer's Disease.

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