A human carboxypeptidase E/NF-alpha 1 gene mutation in an Alzheimer's disease patient leads to dementia and depression in mice

2016-12-06
Cheng, Y.
Cawley, N. X.
Yanık, Tülin
Murthy, S. R. K.
Liu, C.
Kasikci, F.
Abebe, D.
Loh, Y. P.
Show full item record
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
183
views
131
downloads
Patients with Alzheimer's disease (AD), a common dementia among the aging population, often also suffer from depression. This comorbidity is poorly understood. Although most forms of AD are not genetically inherited, we have identified a new human mutation in the carboxypeptidase E (CPE)/neurotrophic factor-alpha 1 (NF-alpha 1) gene from an AD patient that caused memory deficit and depressive-like behavior in transgenic mice. This mutation consists of three adenosine inserts, introducing nine amino acids, including two glutamines into the mutant protein, herein called CPE-QQ. Expression of CPE-QQ in Neuro2a cells demonstrated that it was not secreted, but accumulated in the endoplasmic reticulum and was subsequently degraded by proteasomes. Expression of CPE-QQ in rat hippocampal neurons resulted in cell death, through increased ER stress and decreased expression of pro-survival protein, BCL-2. Transgenic mice expressing CPE-QQ did not show any difference in the processing enzyme activity of CPE compared with wild-type mice. However, the transgenic mice exhibited poor memory, depressive-like behavior, severely decreased dendrites in the hippocampal CA3 region and medial prefrontal cortex indicative of neurodegeneration, hyperphosphorylation of tau at Ser(396), and diminished neurogenesis in the dentate gyrus at 50 weeks old. All these pathologies are associated with AD and the latter with depression and were observed in 50-week-old mice. Interestingly, the younger CPE-QQ mice (11 weeks old) did not show deficits in dendrite outgrowth and neurogenesis. This study has uncovered a human CPE/NF-alpha 1 gene mutation that could lead to comorbidity of dementia and depression, emphasizing the importance of this gene in cognitive function.
HIPPOCAMPAL NEUROGENESIS, MEMORY DEFICITS, TAU, ANTIDEPRESSANTS, PHOSPHORYLATION, NEUROPROTECTION, DEGENERATION, EPIGENETICS, CONVERTASE, TANGLES
https://hdl.handle.net/11511/37216
TRANSLATIONAL PSYCHIATRY
Department of Biology, Article

Suggestions

COMPARATIVE ANALYSIS OF BRAIN CELL CULTURES AND TISSUES IN ALZHEIMER’S DISEASE BASED ON DIFFERENTIAL EXPRESSION AND GENE SET ENRICHMENT
Burduroğlu, Hüseyin Cahit; Aydın Son, Yeşim; Department of Bioinformatics (2023-1-25)
Alzheimer’s disease is currently the most common cause of dementia in the world. It is a neurodegenerative disease that is diagnosed neuropathologically by observing B-amyloid plaques and neurofibrillary tangles in the brain. Transcriptional differentiations, protein regulations, and the interactions in between have been investigated by recent studies to understand from which brain cell type the disease stems, such as microglia, astrocytes, and neurons. These studies are mostly performed on brain tiss...
Investigating conversion from mild cognitive impairment to alzheimer's disease using latent space manipulation
Ayvaz, Deniz Sezin; Baytaş, İnci M. (Orta Doğu Teknik Üniversitesi Enformatik Enstitüsü; 2022-10)
Alzheimer’s disease, a progressive neurologic disorder, is the most common cause of dementia, affecting millions worldwide. Mild Cognitive Impairment (MCI) is considered an intermediate stage before Alzheimer's. Early prediction of the conversion from MCI to Alzheimer's is crucial to take necessary precautions for decelerating the disease progression and developing suitable treatments. This study proposes a deep learning framework to identify patients whose diagnoses might change from MCI to Alzheimer’s in ...
Effects Of Enhanced TrkB Signaling In Mouse Embryonic Stem Cell-Derived Cortical Neurons Against Amyloid Beta 42-Mediated Cellular Events
Beşarat, Peri; Kiriş, Erkan; Department of Biology (2023-1-20)
Alzheimer’s Disease (AD) is the sixth most common cause of death globally. The disease causes memory loss and cognitive decline, eventually preventing the individual from performing simple actions in daily life. 2014-2018 Report of The Turkish Association of Alzheimer's indicates that there are at least 600,000 AD patients in Turkey and this number is expected to increase due to the rapidly aging population since AD is highly age-dependent. Despite extensive studies, there is currently no disease-modifying ...
Fluorescent labeling of SPOCK1 and localization studies in live neural cell lines
Karaboğa, Zeynep Eda; Son, Çağdaş Devrim; Aydın Son, Yeşim; Department of Biology (2022-11-30)
Alzheimer's disease is the most common form of dementia and is incurable. The late onset Alzheimer’s disease (LOAD) is associated with complex genetic transition, and the molecular background has not been enlightened yet. Our previous research on the meta-analysis of genome-wide association studies (GWAS) showed a statistical correlation between SPOCK1 variants and LOAD. Also, it is co-regulated with apolipoprotein (APP), one of the proteins clinically linked with LOAD. Furthermore, the SPOCK1 protein ...
Gene-level pathogenicity scores for alzheimer’s disease using genomic variants from rna-seq data
Bozkurt, Fatma Betül; İlgün, Atılay; Uzuner, Dilara; Çakır, Tunahan (Orta Doğu Teknik Üniversitesi Enformatik Enstitüsü; 2022-10)
Alzheimer’s disease (AD) is a complex neurodegenerative disorder affecting millions of people worldwide. Next-generation sequencing technologies such as whole-exome/genome sequencing have been widely used for detecting the variants in the genome to understand the disease etiology and unravel underlying molecular mechanisms. Alternatively, RNA-Seq data can also be used to detect variants. Since AD is a complex disease, several variants are involved in the disease pathogenesis. By using scoring algorithms, it...
Citation Formats
Y. Cheng et al., “A human carboxypeptidase E/NF-alpha 1 gene mutation in an Alzheimer’s disease patient leads to dementia and depression in mice,” TRANSLATIONAL PSYCHIATRY, pp. 0–0, 2016, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/37216.
METU IIS - Integrated Information Service open@metu.edu.tr