Dataset Information

Multi-omics characterization of SIRT3 metabolism and its adaptation to the presence of amyloid-beta oligomers in nasal epithelial cells

ABSTRACT: Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylases that regulate cellular homeostasis in a multifactorial manner. Although alterations in SIRT signaling are evidenced in both olfactory dysfunction and Alzheimer’s disease (AD), the specific role of sirtuin 3 (SIRT3) in olfactory metabolism remains unknown. Here, we have evidenced a partial interdependency between SIRT3 and SIRT5 deacetylase members in human nasal epithelial cell cultures (hNECs). A multi-omic integrative approach applied to conditions of SIRT3 silencing or overexpression revealed that hNEC metabolism is markedly more sensitive to reduced SIRT3 levels, identifying specific transcripts and phosphorylation sites belonging to inflammatory and redox mediators that are tightly regulated by SIRT3 in hNECs. Following exposure to oligomeric Aβ peptide, phosphoproteomic alterations promoted an activation trend of stress-induced senescence and apoptotic signaling in SIRT3-silenced hNECs, whereas induced activation of mitotic phase–related pathways, Hippo signaling, and glycogen metabolism were evidenced in SIRT3-overexpressing hNECs. From a translational point of view, a dissimilar sex-dependent profile in serum SIRT protein levels (SIRT1 and SIRT6) was observed across multiple neurological disorders including AD, mixed dementia, frontotemporal lobar degeneration and amyotrophic lateral sclerosis. These data shed new light on novel SIRT-dependent mechanisms associated with neurodegeneration, underscoring that the maintenance of optimal SIRT3 protein levels may partially counteract the detrimental effects induced by Aβ oligomers in AD at olfactory level.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324335 | GEO | 2026/03/14

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Scope: As a result of population ageing, the number of Alzheimer’s disease (AD) patients has rapidly increased. There are many hypothesises on the pathogenesis of AD, but its detailed molecular mechanism is still unknown, and so no effective preventive or therapeutic measures have been established. Some reports showed a decrease in levels of norepinephrine (NE) has been suspected to be involved in the decline of cognitive function in AD patients and NE concentrations were decreased in postmortem AD patient brains. Tyr-Trp was identified as being the most effective dipeptide in enhancing norepinephrine (NE) synthesis and metabolism. And Tyr-Trp treatment ameliorated the short-term memory dysfunction in AD model mice caused by amyloid beta (Aβ) 25-35. So, the purpose of this study was to investigate the preventive or/and protective effects of Tyr-Trp administration in AD model mice. Methods and results: ddY mice were fed normal diet. After 7 days of feeding, mice were divided into 3 groups (n=10 per group) as follows: the sham group, which received saline administration and distilled water injection; the Aβ group, which received saline administration and Aβ peptides 25–35 injection; and the Aβ+YW group, which received Tyr-Trp administration and Aβ peptides 25–35 injection. Tyr-Trp was orally administered Tyr-Trp (100 mg kg-1 day-1, twice a day), starting 7 days before Aβ peptides injection. The other groups received oral administration of saline (5 mL kg-1). After Aβ peptides injection or sham operation, each groups received every oral administration. DAN microarray showed that Tyrosine hydroxylase, dopa decarboxylase and dopamine receptor D2 mRNA expressions which were downregulated in Aβ group comparing with sham group were upregulated in Aβ+YW group comparing with Aβ group. In addition, quinoid dihydropteridine reductase mRNA expression which wasn’t changed in Aβ group comparing with sham group was upregulated in Aβ+YW group comparing with Aβ group. Conclusions: These results suggest that Tyr-Trp administration might ameliorate the short-term memory dysfunction in AD model mice because of enhancing norepinephrine (NE) synthesis and metabolism through metabolism of both Tyr and Trp.

Project description:Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer’s disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of animal model of AD. Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aβ-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR). Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and hypertrophic reactive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Ab aggregates in the brain of APP/PS1 mice An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients. Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.

Dataset Information

Multi-omics characterization of SIRT3 metabolism and its adaptation to the presence of amyloid-beta oligomers in nasal epithelial cells

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets