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Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer’s disease
Alzheimer’s disease (AD) is complex and highly heterogeneous. Less than 10% of AD cases are early-onset (EOAD) caused by autosomal dominantly inherited mutations in amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2), each of which can increase Aβ generation and, thus, amyloid...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9344928/ https://www.ncbi.nlm.nih.gov/pubmed/35928571 http://dx.doi.org/10.3389/fncel.2022.954071 |
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author | Wang, Hongjie Devadoss, Dinesh Nair, Madhavan Chand, Hitendra S. Lakshmana, Madepalli K. |
author_facet | Wang, Hongjie Devadoss, Dinesh Nair, Madhavan Chand, Hitendra S. Lakshmana, Madepalli K. |
author_sort | Wang, Hongjie |
collection | PubMed |
description | Alzheimer’s disease (AD) is complex and highly heterogeneous. Less than 10% of AD cases are early-onset (EOAD) caused by autosomal dominantly inherited mutations in amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2), each of which can increase Aβ generation and, thus, amyloid plaques. The remaining 90% of cases of AD are late-onset (LOAD) or sporadic. Intense research efforts have led to identification of many genes that increase the risk of AD. An IQ motif containing protein K (IQCK) was recently identified by several investigators as an Alzheimer’s disease risk gene. However, how IQCK increases AD risk is completely unknown. Since IQCK is a novel gene, there is limited information on its physiological characterization. To understand its role in AD, it is first important to determine its subcellular localization, whether and where it is expressed in the brain, and what type of brain cells express the IQCK protein. Therefore, in this study, we show by immunocytochemical (ICC) staining that IQCK is expressed in both the nucleus and the cytoplasm of SH-SY5Y neuroblastoma cells as well as HeLa cells but not in either HMC3 microglial or CHO cells. By immunohistochemistry (IHC), we also show that IQCK is expressed in both mouse and human neurons, including neuronal processes in vivo in the mouse brain. IHC data also show that the IQCK protein is widely expressed throughout the mouse brain, although regional differences were noted. IQCK expression was highest in the brainstem (BS), followed by the cerebellum (CB) and the cortex (CX), and it was lowest in the hippocampus (HP). This finding was consistent with data from an immunoblot analysis of brain tissue homogenates. Interestingly, we found IQCK expression in neurons, astrocytes, and oligodendrocytes using cell-specific antibodies, but IQCK was not detected in microglial cells, consistent with negative in vitro results in HMC3 cells. Most importantly, we found that actin-normalized IQCK protein levels were increased by 2 folds in AD brains relative to normal control (NC) brains. Furthermore, the IQCK protein was found in amyloid plaques, suggesting that IQCK may play a pathogenic role in either Aβ generation or amyloid plaque deposition in AD. |
format | Online Article Text |
id | pubmed-9344928 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93449282022-08-03 Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer’s disease Wang, Hongjie Devadoss, Dinesh Nair, Madhavan Chand, Hitendra S. Lakshmana, Madepalli K. Front Cell Neurosci Neuroscience Alzheimer’s disease (AD) is complex and highly heterogeneous. Less than 10% of AD cases are early-onset (EOAD) caused by autosomal dominantly inherited mutations in amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2), each of which can increase Aβ generation and, thus, amyloid plaques. The remaining 90% of cases of AD are late-onset (LOAD) or sporadic. Intense research efforts have led to identification of many genes that increase the risk of AD. An IQ motif containing protein K (IQCK) was recently identified by several investigators as an Alzheimer’s disease risk gene. However, how IQCK increases AD risk is completely unknown. Since IQCK is a novel gene, there is limited information on its physiological characterization. To understand its role in AD, it is first important to determine its subcellular localization, whether and where it is expressed in the brain, and what type of brain cells express the IQCK protein. Therefore, in this study, we show by immunocytochemical (ICC) staining that IQCK is expressed in both the nucleus and the cytoplasm of SH-SY5Y neuroblastoma cells as well as HeLa cells but not in either HMC3 microglial or CHO cells. By immunohistochemistry (IHC), we also show that IQCK is expressed in both mouse and human neurons, including neuronal processes in vivo in the mouse brain. IHC data also show that the IQCK protein is widely expressed throughout the mouse brain, although regional differences were noted. IQCK expression was highest in the brainstem (BS), followed by the cerebellum (CB) and the cortex (CX), and it was lowest in the hippocampus (HP). This finding was consistent with data from an immunoblot analysis of brain tissue homogenates. Interestingly, we found IQCK expression in neurons, astrocytes, and oligodendrocytes using cell-specific antibodies, but IQCK was not detected in microglial cells, consistent with negative in vitro results in HMC3 cells. Most importantly, we found that actin-normalized IQCK protein levels were increased by 2 folds in AD brains relative to normal control (NC) brains. Furthermore, the IQCK protein was found in amyloid plaques, suggesting that IQCK may play a pathogenic role in either Aβ generation or amyloid plaque deposition in AD. Frontiers Media S.A. 2022-07-19 /pmc/articles/PMC9344928/ /pubmed/35928571 http://dx.doi.org/10.3389/fncel.2022.954071 Text en Copyright © 2022 Wang, Devadoss, Nair, Chand and Lakshmana. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Wang, Hongjie Devadoss, Dinesh Nair, Madhavan Chand, Hitendra S. Lakshmana, Madepalli K. Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer’s disease |
title | Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer’s disease |
title_full | Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer’s disease |
title_fullStr | Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer’s disease |
title_full_unstemmed | Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer’s disease |
title_short | Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer’s disease |
title_sort | novel alzheimer risk factor iq motif containing protein k is abundantly expressed in the brain and is markedly increased in patients with alzheimer’s disease |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9344928/ https://www.ncbi.nlm.nih.gov/pubmed/35928571 http://dx.doi.org/10.3389/fncel.2022.954071 |
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