Transcriptomics and mechanistic elucidation of Alzheimer's disease risk genes in the brain and in vitro models
Abstract
In this study, we have assessed the expression and splicing status of genes involved in the pathogenesis or affecting the risk of Alzheimer's disease (AD) in the postmortem inferior temporal cortex samples obtained from 60 subjects with varying degree of AD-related neurofibrillary pathology. These subjects were grouped based on neurofibrillary pathology into 3 groups: Braak stages 0-II, Braak stages III-IV, and Braak stages V-VI. We also examined the right frontal cortical biopsies obtained during life from 22 patients with idiopathic shunt-responding normal pressure hydrocephalus, a disease that displays similar pathologic alterations as seen in AD. These 22 patients were categorized according to dichotomized amyloid-β positive or negative pathology in the biopsies. We observed that the expression of FRMD4A significantly decreased, and the expression of MS4A6A significantly increased in relation to increasing AD-related neurofibrillary pathology. Moreover, the expression of 2 exons in both CLU and TREM2 significantly increased with increase in AD-related neurofibrillary pathology. However, a similar trend toward increased expression in CLU and TREM2 was observed with most of the studied exons, suggesting a global change in the expression rather than altered splicing. Correlation of gene expression with well-established AD-related factors, such as α-, β-, and γ-secretase activities, brain amyloid-β42 levels, and cerebrospinal fluid biomarkers, revealed a positive correlation…
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Two studies reported significantly increased BIN1 transcript levels in brains of individuals with AD.
“While two studies have reported significantly increased BIN1 transcripts levels in brains of individuals with AD [26, 31]”
From Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts (2016) · cites this paper as [31]
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De Rossi, P., Buggia-Prévot, V., Clayton, B. L. L., Vasquez, J. B., van Sanford, C., Andrew, R. J., Lesnick, R., Botté, A., Deyts, C., Salem, S., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0124-1 · Cited by 151 · see citing works
“While two studies have reported significantly increased BIN1 transcripts levels in brains of individuals with AD [26, 31], another found a positive correlation between BIN1 expression levels and later age at onset of the disease [28].”
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- Authors
- Martiskainen, H., Viswanathan, J., Nykänen, N.-P., Kurki, M., Helisalmi, S., Natunen, T., Sarajärvi, T., Kurkinen, K. M. A., Pursiheimo, J.-P., Rauramaa, T., Alafuzoff, I., Jääskeläinen, J. E., Leinonen, V., Soininen, H., Haapasalo, A., Huttunen, H. J., & Hiltunen, M.
- Affiliations
- University of Eastern Finland (FI)
- University of Helsinki (FI)
- University of Turku (FI)
- Uppsala University (SE)
- Corresponding author
- Hiltunen, Mikko
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 36
- Issue
- 2
- Pages
- 1221.e15-1221.e28
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2000714006
- Cited by
- 70
- References
- 11
- Citations by year
- 2025: 6 · 2024: 17 · 2023: 5 · 2022: 7 · 2021: 7 · 2020: 4 · 2019: 4 · 2018: 7 · 2017: 2 · 2016: 9 · 2015: 2
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Suomen Akatemia (218081, 263762, 126889)
- Suomen Kulttuurirahasto
- EVO (5772708)
- Strategic Funding of the University of Eastern Finland
- Sigrid Juselius Foundation
- VPH Dementia Research Enabled by IT (601055)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, Alzheimer's disease risk genes, gene expression, alternative splicing, neurofibrillary pathology, MS4A6A, clusterin, TREM2, BIN1, amyloid-beta 42, tau phosphorylation, normal pressure hydrocephalus, expression quantitative trait loci, inferior temporal cortex, Braak stages
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Male, Membrane Glycoproteins, Membrane Proteins, Neurofibrils, Nuclear Proteins, Phosphorylation, Receptors, Immunologic, Risk, Gene Expression, Amyloid beta-Peptides, tau Proteins, Genetic Predisposition to Disease, Gene Expression Profiling, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, Amyloid Precursor Protein Secretases, Transcriptome, In Vitro Techniques
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