Amyloidosis causes downregulation of SorLA, SorCS1 and SorCS3 expression in mice
Guido Hermey1, Sabine A Hoffmeister-Ullerich2, Barbara Merz1
1Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, D-20251 Hamburg, Germany.
Abstract:
Accumulation of β-amyloid peptide (Aβ) is regarded as a primary cause of Alzheimer's disease (AD). Aβ is derived by sequential cleavage of the amyloid precursor protein (APP). Alterations in the subcellular targeting of APP are thought to affect the degree of Aβ production. Sorting receptors, such as SorLA, convey subcellular targeting of APP. Dysfunction of SorLA, and likely of the related receptors SorCS1 and SorCS3, cause AD. Nevertheless, disease progression could also provoke altered expression of the receptors. Here, we assessed if Aβ plaque formation promotes altered expression of SorLA, SorCS1 and SorCS3. We analyzed transcript levels during aging and after amyloidosis in brain areas characterized by early amyloid plaque formation in an AD mouse model (APPPS1) and wild types. We observed stable expression levels during aging (1-12 months). After plaque formation, SorCS1 and SorLA expression were markedly reduced in the frontal cerebral cortex and to a minor extent in the hippocampus, whereas SorCS3 expression was solely reduced in the frontal cerebral cortex. Our results indicate that disease progression, associated with Aβ accumulation, can negatively regulate expression of the receptors.
Insights
Alzheimer's disease (AD) involves β-amyloid peptide (Aβ) accumulation. This study shows Aβ plaque formation reduces expression of key APP-sorting receptors SorLA, SorCS1, and SorCS3 in AD mouse models.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) is linked to β-amyloid peptide (Aβ) accumulation.
- Amyloid precursor protein (APP) cleavage produces Aβ, and its subcellular targeting influences Aβ production.
- Receptors like SorLA, SorCS1, and SorCS3 regulate APP targeting and their dysfunction is implicated in AD.
Purpose of the Study:
- To investigate if Aβ plaque formation alters the expression of SorLA, SorCS1, and SorCS3.
- To determine the impact of aging and amyloidosis on these receptor levels in specific brain regions.
Main Methods:
- Analysis of transcript levels in an APPPS1 AD mouse model and wild-type controls.
- Comparison of gene expression during aging (1-12 months) and after amyloid plaque formation.
- Focus on brain areas with early amyloid plaque development, including the frontal cerebral cortex and hippocampus.
Main Results:
- Receptor expression remained stable during normal aging (1-12 months).
- Following Aβ plaque formation, SorCS1 and SorLA expression significantly decreased in the frontal cortex and hippocampus.
- SorCS3 expression was reduced specifically in the frontal cortex after plaque development.
Conclusions:
- Aβ accumulation during Alzheimer's disease progression negatively regulates the expression of SorLA, SorCS1, and SorCS3.
- Altered expression of these APP-sorting receptors may contribute to AD pathogenesis.
- Findings highlight a potential feedback mechanism where disease pathology impacts the expression of key regulatory proteins.
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