Expression of SORL1 and a novel SORL1 splice variant in normal and Alzheimers disease brain
Open accessAbstract
Background: Variations in sortilin-related receptor (SORL1) expression and function have been implicated in Alzheimers Disease (AD). Here, to gain insights into SORL1, we evaluated SORL1 expression and splicing as a function of AD and AD neuropathology, neural gene expression and a candidate single nucleotide polymorphism (SNP). Results: To identify SORL1 splice variants, we scanned each of the 46 internal SORL1 exons in human brain RNA samples and readily found SORL1 isoforms that lack exon 2 or exon 19. Quantification in a case-control series of the more abundant isoform lacking exon 2 (delta-2-SORL1), as well as the "full-length" SORL1 (FL-SORL1) isoform containing exon 2 showed that expression of FL-SORL1 was reduced in AD individuals. Moreover, FL-SORL1 was reduced in cognitively intact individuals with significant AD-like neuropathology. In contrast, the expression of the delta-2-SORL1 isoform was similar in AD and non-AD brains. The expression of FL-SORL1 was significantly associated with synaptophysin expression while delta-2-SORL1 was modestly enriched in white matter. Lastly, FL-SORL1 expression was associated with rs661057, a SORL1 intron one SNP that has been associated with AD risk. A linear regression analysis found that rs661057, synaptophysin expression and AD neuropathology were each associated with FL-SORL1 expression. Conclusion: These results confirm that FL-SORL1 expression declines in AD and with AD-associated neuropathology, suggest that FL-SORL1 declines in cognitively-intact individuals with AD-associated neuropathology, identify a novel SORL1 splice variant that is expressed similarly in AD and non-AD individuals, and provide evidence that an AD-associated SNP is associated with SORL1 expression. Overall, these results contribute to our understanding of SORL1 expression in the human brain.
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SORL1 is a sorting receptor located in neurons, astrocytes, and microglia and is known to direct APP toward non-amyloidogenic processing in the trans-Golgi network.
“SORL1, a sorting receptor located in neurons [152], astrocytes, and microglia [153] is known to direct APP toward non-amyloidogenic processing in the trans-Golgi network [148, 154].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [152]
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References 28 · Cited by 56
- Authors
- Grear, K. E., Ling, I.-F., Simpson, J. F., Furman, J. L., Simmons, C. R., Peterson, S. L., Schmitt, F. A., Markesbery, W. R., Liu, Q., Crook, J. E., Younkin, S. G., Bu, G., & Estus, S.
- Affiliations
- University of Kentucky (US)
- Washington University in St. Louis (US)
- Mayo Clinic (US)
- Corresponding author
- Estus, Steven
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2009-11-04
- Volume
- 4
- Issue
- 1
- Pages
- 46-46
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC2776013
- OpenAlex
- W2123056267
- Cited by
- 56
- References
- 28
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 5 · 2015: 3 · 2014: 5 · 2013: 4 · 2012: 8
- FWCI
- 3.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- University of Kentucky
- National Institutes of Health
- National Institute on Aging (P01AG030128, P30AG028383, R01AG031784, R01AG026147, R01AG035355)
- 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
- SORL1, Alzheimer's disease, alternative splicing, single nucleotide polymorphisms, synaptophysin, white matter, cognitive impairment
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