APOE Gene Expression in Patients with Alzheimer’s Disease

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

Download Full-text

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

Nature Communications ◽

10.1038/s41467-021-22399-3 ◽

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.

Download Full-text

P1-102: Building a Testable Mathematical Model for Alzheimer’s Disease Using Gene Expression Changes and Biochemical Systems Theory (BST)

Alzheimer s & Dementia ◽

10.1016/j.jalz.2016.06.850 ◽

2016 ◽

Vol 12 ◽

pp. P440-P441

Author(s):

Randolph A. Coleman ◽

Ceyda Durmaz ◽

Alec A. Weech ◽

Frank J. Castora

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Mathematical Model ◽

Alzheimer's Disease ◽

Systems Theory ◽

Biochemical Systems Theory ◽

Biochemical Systems

Download Full-text

Comprehensive Analysis of Differential Expression Profiles of Long Non-coding RNAs with Associated Co-expression and Competing Endogenous RNA Networks in the Hippocampus of Patients with Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205018666211202143449 ◽

2021 ◽

Vol 18 ◽

Author(s):

Jian-Jun Zhang ◽

Ze-Xuan-Zhu ◽

Guang-Min-Xu ◽

Peng Su ◽

Qian Lei ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Expression Profiles ◽

Gene Expression Omnibus ◽

Competing Endogenous Rna ◽

Pathogenic Genes ◽

Non Coding Rna ◽

Using Data ◽

Trans Regulation

Background: Alzheimer's disease (AD) is still one of the major threats to human health. Although a satisfactory treatment for AD has not yet been discovered, it is necessary to continue to search for novel approaches to deal with this insidious and debilitating disease. Although numerous studies have shown that long non-coding RNA (lncRNA) occupy a significant role in a variety of diseases, their roles in AD remain unclear. Objectives: Using data analysis to explore the role of lncRNA in the course of AD, to further our understanding of AD, and to look forward to finding a new breakthrough for the treatment of AD. Methods: We downloaded and screened expression data of the hippocampal regions of patients with AD from the Gene Expression Omnibus database. We generated lncRNA-miRNA-mRNA networks based on the competing endogenous RNA (ceRNA) hypothesis, and according to gene expression level, we constructed a coding-noncoding co-expression (CNC) network and then executed cis- and trans-regulation analyses. Results: Through comprehensive and systematic analyses, we found that lncRNAs MALAT1, OIP5-AS1, LINC00657, and lnc-NUMB-1 regulated the expression of the key AD pathogenic genes APP, PSEN1, BACE1; and that these lncRNAs may promote the distribution of β-amyloid (Aβ protein) in the brain through exosomes. In addition, lncRNAs were found to adjust viral transcriptional expression, thereby further supporting viral pathogenesis for AD. Conclusions: The lncRNAs MALAT1, OIP5-AS1, LINC00657, and lnc-NUMB-1 that are present in the hippocampus of AD patients exert an important influence on the development of this disease.

Download Full-text