Iron Responsive Element-Mediated Responses to Iron Dyshomeostasis in Alzheimer’s Disease

2021 ◽  
pp. 1-34
Author(s):  
Nhi Hin ◽  
Morgan Newman ◽  
Stephen Pederson ◽  
Michael Lardelli
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cultured Cells ◽  
Transcript Abundance ◽  
Untranslated Regions ◽  
Gene Sets ◽  
The Stability ◽  
Responsive Element ◽  
Iron Responsive Elements

Background: Iron trafficking and accumulation is associated with Alzheimer’s disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterized, making it difficult to explore these in existing datasets. Objective: To identify sets of genes predicted to contain iron responsive elements (IREs) and use these to explore possible iron dyshomeostasis-associated gene expression responses in AD. Methods: Comprehensive sets of genes containing predicted IRE or IRE-like motifs in their 3′ or 5′ untranslated regions (UTRs) were identified in human, mouse, and zebrafish reference transcriptomes. Further analyses focusing on these genes were applied to a range of cultured cell, human, mouse, and zebrafish gene expression datasets. Results: IRE gene sets are sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, changes in IRE transcript abundance are among the earliest observable changes in zebrafish familial AD (fAD)-like brains, preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some IREs in the 3′ untranslated regions of transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead display decreased stability, indicating that this is not a generalizable paradigm. Conclusion: Our results reveal IRE gene expression changes as early markers of the pathogenic process in fAD and are consistent with iron dyshomeostasis as an important driver of this disease. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis-associated gene expression responses across different species, tissues, and conditions.

scholarly journals Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

2020 ◽  
Author(s):  
Nhi Hin ◽  
Morgan Newman ◽  
Stephen Pederson ◽  
Michael Lardelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Iron Overload ◽  
Cultured Cells ◽  
Transcript Abundance ◽  
Gene Sets ◽  
Post Mortem Brain ◽  
The Stability ◽  
Responsive Element ◽  
Iron Responsive Elements

AbstractBackgroundIron trafficking and accumulation has been associated with Alzheimer’s disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterised, making it difficult to explore these in existing datasets.ResultsWe identified sets of genes predicted to contain Iron Responsive Elements (IREs), and used these to explore iron dyshomeostasis responses in transcript datasets involving (1) cultured cells under iron overload and deficiency treatments, (2) post-mortem brain tissues from AD and other neuropathologies, (3) 5XFAD transgenic mice modelling AD pathologies, and (4) a zebrafish knock-in model of early-onset, familial AD (fAD). IRE gene sets were sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, we see changes in 3’ IRE transcript abundance as amongst the earliest observable in zebrafish fAD-like brains and preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some 3’ IRE transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead show decreased stability, indicating that this is not a generalizable paradigm.ConclusionsOur results reveal iron dyshomeostasis as a likely early driver of fAD and as able to distinguish AD from other brain pathologies. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis responses in different species, tissues, and conditions.

scholarly journals Alzheimer’s disease brain contains tau fractions with differential prion-like activities

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Longfei Li ◽  
Ruirui Shi ◽  
Jianlan Gu ◽  
Yunn Chyn Tung ◽  
Yan Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cultured Cells ◽  
Regional Distribution ◽  
Proteinase K ◽  
Hyperphosphorylated Tau ◽  
Terminal Portion ◽  
Tau Pathology ◽  
Heat Stable ◽  
Tau Aggregation

AbstractNeurofibrillary tangles (NFTs) made of abnormally hyperphosphorylated tau are a hallmark of Alzheimer’s disease (AD) and related tauopathies. Regional distribution of NFTs is associated with the progression of the disease and has been proposed to be a result of prion-like propagation of misfolded tau. Tau in AD brain is heterogenous and presents in various forms. In the present study, we prepared different tau fractions by sedimentation combined with sarkosyl solubility from AD brains and analyzed their biochemical and pathological properties. We found that tau in oligomeric fraction (O-tau), sarkosyl-insoluble fractions 1 and 2 (SI1-tau and SI2-tau) and monomeric heat-stable fraction (HS-tau) showed differences in truncation, hyperphosphorylation, and resistance to proteinase K. O-tau, SI1-tau, and SI2-tau, but not HS-tau, were hyperphosphorylated at multiple sites and contained SDS- and β-mercaptoethanol–resistant high molecular weight aggregates, which lacked the N-terminal portion of tau. O-tau and SI2-tau displayed more truncation and less hyperphosphorylation than SI1-tau. Resistance to proteinase K was increased from O-tau to SI1-tau to SI2-tau. O-tau and SI1-tau, but not SI2-tau or HS-tau, captured tau from cell lysates and seeded tau aggregation in cultured cells. Heat treatment could not kill the prion-like activity of O-tau to capture normal tau. Hippocampal injection of O-tau into 18-month-old FVB mice induced significant tau aggregation in both ipsilateral and contralateral hippocampi, but SI1-tau only induced tau pathology in the ipsilateral hippocampus, and SI2-tau and HS-tau failed to induce any detectable tau aggregation. These findings suggest that O-tau and SI1-tau have prion-like activities and may serve as seeds to recruit tau and template tau to aggregate, resulting in the propagation of tau pathology. Heterogeneity of tau pathology within AD brain results in different fractions with different biological and prion-like properties, which may pose a major challenge in targeting tau for development of effective therapeutic treatments.

scholarly journals Association of neurogranin gene expression with Alzheimer's disease pathology in the perirhinal cortex

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Xiaoyan Sun ◽  
Qian Wang ◽  
Kaj Blennow ◽  
Henrik Zetterberg ◽  
Micheline McCarthy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Perirhinal Cortex

Lentivirus-Mediated Expression of Human Secreted Amyloid Precursor Protein-Alpha Promotes Long-Term Induction of Neuroprotective Genes and Pathways in a Mouse Model of Alzheimer’s Disease

2020 ◽  
pp. 1-16
Author(s):  
Margaret Ryan ◽  
Valerie T.Y. Tan ◽  
Nasya Thompson ◽  
Diane Guévremont ◽  
Bruce G. Mockett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Integrated Analysis ◽  
Empty Vector ◽  
Mouse Transcriptome

Background: Secreted amyloid precursor protein-alpha (sAPPα) can enhance memory and is neurotrophic and neuroprotective across a range of disease-associated insults, including amyloid-β toxicity. In a significant step toward validating sAPPα as a therapeutic for Alzheimer’s disease (AD), we demonstrated that long-term overexpression of human sAPPα (for 8 months) in a mouse model of amyloidosis (APP/PS1) could prevent the behavioral and electrophysiological deficits that develop in these mice. Objective: To explore the underlying molecular mechanisms responsible for the significant physiological and behavioral improvements observed in sAPPα-treated APP/PS1 mice. Methods: We assessed the long-term effects on the hippocampal transcriptome following continuous lentiviral delivery of sAPPα or empty-vector to male APP/PS1 mice and wild-type controls using Affymetrix Mouse Transcriptome Assays. Data analysis was carried out within the Affymetrix Transcriptome Analysis Console and an integrated analysis of the resulting transcriptomic data was performed with Ingenuity Pathway analysis (IPA). Results: Mouse transcriptome assays revealed expected AD-associated gene expression changes in empty-vector APP/PS1 mice, providing validation of the assays used for the analysis. By contrast, there were specific sAPPα-associated gene expression profiles which included increases in key neuroprotective genes such as Decorin, betaine-GABA transporter, and protocadherin beta-5, subsequently validated by qRT-PCR. An integrated biological pathways analysis highlighted regulation of GABA receptor signaling, cell survival, and inflammatory responses. Furthermore, upstream gene regulatory analysis implicated sAPPα activation of Interleukin-4, which can counteract inflammatory changes in AD. Conclusion: This study identified key molecular processes that likely underpin the long-term neuroprotective and therapeutic effects of increasing sAPPα levels in vivo

scholarly journals Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Angela M. Crist ◽  
Kelly M. Hinkle ◽  
Xue Wang ◽  
Christina M. Moloney ◽  
Billie J. Matchett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Digital Pathology ◽  
Selective Vulnerability ◽  
Brain Regions ◽  
Biochemical Analyses ◽  
The Brain ◽  
Relevant Gene ◽  
Tau Expression

AbstractSelective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer’s disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.

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