Cited by 141Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Loss of LR11/SORLA Enhances Early Pathology in a Mouse Model of Amyloidosis: Evidence for a Proximal Role in Alzheimer's Disease

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Dodson, Sara E., Andersen, Olav M., Karmali, Vinit, Fritz, Jason J., Cheng, Dongmei, Peng, Junmin, Levey, Allan I., Willnow, Thomas E. +1 more·2008·The Journal of Neuroscience

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia, resulting in progressive neuronal death and debilitating damage to brain loci that mediate memory and higher cognitive function. While pathogenic genetic mutations have been implicated in ∼2% of AD cases, the proximal events that underlie the common, sporadic form of the disease are incompletely understood. Converging lines of evidence from human neuropathology, basic biology, and genetics have implicated loss of the multifunctional receptor LR11 (also known as SORLA and SORL1) in AD pathogenesis. Cell-based studies suggest that LR11 reduces the formation of β-amyloid (Aβ), the molecule believed to be a primary toxic species in AD. Recently, mutant mice deficient in LR11 were shown to upregulate murine Aβ in mouse brain. In the current study, LR11-deficient mice were crossed with transgenic mice expressing autosomal-dominant human AD genes, presenilin-1 (PS1ΔE9) and amyloid precursor protein (APPswe). Here, we show that LR11 deficiency in this AD mouse model significantly increases Aβ levels and exacerbates early amyloid pathology in brain, causing a forward shift in disease onset that is LR11 gene dose-dependent. Loss of LR11 increases the processing of the APP holo-molecule into α-, β-, and γ-secretase derived metabolites. We propose that LR11 regulates APP processing and Aβ accumulation in vivo and is of proximal importance to the cascade of pathological amyloidosis. The results of the current study support the hypothesis that control of LR11 expression may exert critical effects on Alzheimer's disease susceptibility in humans.

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Crossref · 10.1523/jneurosci.4582-08.2008

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  • Reduction of LR11/SorLA protein levels increased Aβ levels and exacerbated amyloid plaque pathology in an APP/PSEN1Δ9 mouse model of amyloidosis.

    “Consistent with the previous cell-based studies, reduction of LR11/SorLA protein levels increased Aβ levels and exacerbated amyloid plaque pathology in an APP/PSEN1Δ9 mouse model of amyloidosis (Dodson et al., 2008).”

    From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Dodson et al., 2008

  • Overexpression of SORLA in neuronal cells blocks amyloidogenic processing and reduces Aβ production, whereas loss of SORLA increases extracellular Aβ levels and plaque deposition in several AD mouse models.

    “Overexpression of SORLA in neuronal cells can block amyloidogenic processing and reduce Aβ production [485], whereas loss of SORLA increased extracellular Aβ levels and plaque deposition in several AD mouse models [486, 487].”

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Authors
Dodson, S. E., Andersen, O. M., Karmali, V., Fritz, J. J., Cheng, D., Peng, J., Levey, A. I., Willnow, T. E., & Lah, J. J.
Affiliations
  • Emory University (US)
  • Aarhus University (DK)
  • Max Delbrück Center (DE)
Venue
The Journal of Neuroscience
Published
2008-11-26
Volume
28
Issue
48
Pages
12877-12886
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W1967519462
Cited by
141
References
44
Citations by year
2026: 2 · 2025: 4 · 2024: 4 · 2023: 8 · 2022: 8 · 2021: 9 · 2020: 7 · 2019: 7 · 2018: 9 · 2017: 7 · 2016: 9 · 2015: 12 · 2014: 10 · 2013: 8 · 2012: 12
FWCI
5.64
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
  • Journal of Neuroscience Nursing
Funders
  • Deutsche Forschungsgemeinschaft
  • National Institutes of Health (AG05136)
  • National Institute on Aging (R01AG024214, AG 05136, P50AG005136)
  • National Institute of Neurological Disorders and Stroke (F31NS055881)
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
LR11, SorLA, SORL1, Alzheimer's disease, amyloidosis, amyloid-beta, APP processing, presenilin 1, APPswe, gene dosage, disease onset, transgenic mouse model
MeSH terms
Alzheimer Disease, Amyloidosis, Animals, Brain, Disease Models, Animal, Gene Expression Regulation, Humans, Mice, Transgenic, Neurons, Receptors, LDL, Up-Regulation, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Knockout, Gene Dosage, Genetic Predisposition to Disease, Membrane Transport Proteins, Mice, Plaque, Amyloid

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