Molecular signatures of neurodegeneration in the cortex of PS1/PS2 double knockout mice
Open accessAbstract
BACKGROUND: Familial Alzheimer's disease-linked variants of presenilin (PSEN1 and PSEN2) contribute to the pathophysiology of disease by both gain-of-function and loss-of-function mechanisms. Deletions of PSEN1 and PSEN2 in the mouse forebrain result in a strong and progressive neurodegenerative phenotype which is characterized by both anatomical and behavioral changes. RESULTS: To better understand the molecular changes associated with these morphological and behavioral phenotypes, we performed a DNA microarray transcriptome profiling of the hippocampus and the frontal cortex of the PSEN1/PSEN2 double knock-out mice and littermate controls at five different ages ranging from 2-8 months. Our data suggest that combined deficiencies of PSEN1 and PSEN2 results in a progressive, age-dependent transcriptome signature related to neurodegeneration and neuroinflammation. While these events may progress differently in the hippocampus and frontal cortex, the most critical expression signatures are common across the two brain regions, and involve a strong upregulation of cathepsin and complement system transcripts. CONCLUSION: The observed neuroinflammatory expression changes are likely to be causally linked to the neurodegenerative phenotype observed in mice with compound deletions of PSEN1 and PSEN2. Furthermore, our results suggest that the evaluation of inhibitors of PS/gamma-secretase activity for treatment of Alzheimer's Disease must include close monitoring for signs of calpain-cathepsin system activation.
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Abnormal aggregation of tau protein ultimately leads to the onset and development of neurodegenerative diseases.
“ultimately leading to the onset and development of neurodegenerative diseases.”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [139]
Mutations in PSEN1 and PSEN2 are associated with abnormal tau protein phosphorylation.
“gene mutations in the premature ageing proteins PSEN1, PSEN2 [138,139], and GRN [140,141] have been shown to be associated with abnormal tau protein phosphorylation”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [139]
Abnormal tau protein phosphorylation promotes the abnormal aggregation of tau protein.
“abnormal tau protein phosphorylation, which promotes the abnormal aggregation of tau protein”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [139]
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Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice
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BackgroundGenes and pathways underlying regional and cell type changes in Alzheimer’s disease
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“For example, gene mutations in the premature ageing proteins PSEN1, PSEN2 [138,139], and GRN [140,141] have been shown to be associated with abnormal tau protein phosphorylation, which promotes the abnormal aggregation of tau protein, ultimately leading to the onset and development of…”
BackgroundMicroRNA Profiling in Aging Brain of PSEN1/PSEN2 Double Knockout Mice
Ham, S., Kim, T. K., Lee, S., Tang, Y.-P., & Im, H.-I. (2018) · Molecular Neurobiology · doi:10.1007/s12035-017-0753-6 · Cited by 12 · see citing works
- Authors
- Mirnics, K., Norstrom, E. M., Garbett, K., Choi, S., Zhang, X., Ebert, P., & Sisodia, S. S.
- Affiliations
- Vanderbilt University (US)
- University of Chicago (US)
- Corresponding author
- Mirnics, Károly
- Sisodia, Sangram S
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2008
- Volume
- 3
- Issue
- 1
- Pages
- 14
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC2569036
- OpenAlex
- W2097778960
- Cited by
- 23
- References
- 46
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 2 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ellison Medical Foundation
- Eisai
- National Institutes of Health (NIH-R01)
- University of California, Irvine
- National Institute on Aging (R01AG027854)
- National Institute of Mental Health (K02MH070786)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- presenilin 1, presenilin 2, familial Alzheimer's disease, neurodegeneration, neuroinflammation, gene expression profiling, frontal cortex, hippocampus, cathepsins, complement system, gamma-secretase inhibitors, age-related gene expression
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