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COL25A1 triggers and promotes Alzheimer's disease-like pathology in vivo.

Tong Y, Xu Y, Scearce-Levie K, Ptácek LJ, Fu YH - Neurogenetics (2009)

Bottom Line: COL25A1 alleles have been associated with increased risk for AD in a Swedish population.These findings demonstrate that COL25A1 leads to AD-like pathology in vivo.Modulation of COL25A1 function may represent an alternative therapeutic intervention for AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of California San Francisco, 1550 Fourth Street, Rock Hall Rm548, San Francisco, CA, 94158, USA.

ABSTRACT
Collagen XXV alpha 1 (COL25A1) is a collagenous type II transmembrane protein purified from senile plaques of Alzheimer's disease (AD) brains. COL25A1 alleles have been associated with increased risk for AD in a Swedish population. COL25A1 is specifically expressed in neurons and binds to aggregated Abeta in vitro. However, its contribution to the pathogenesis of AD and in vivo function are unknown. Here, we report that over-expression of COL25A1 in transgenic mice increases p35/p25 and beta-site APP-cleaving enzyme 1 (BACE1) levels, facilitates intracellular aggregation and extracellular matrix deposits of Abeta, and causes synaptophysin loss and astrocyte activation. COL25A1 mice displayed reduced anxiety-like behavior in elevated plus maze and open field tests and significantly slower swimming speed in Morris water maze. In stable cell lines, motifs in noncollagenous domains of COL25A1 were important for the induction of BACE1 expression. These findings demonstrate that COL25A1 leads to AD-like pathology in vivo. Modulation of COL25A1 function may represent an alternative therapeutic intervention for AD.

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Related in: MedlinePlus

COL25A1 expression in TG mice begins in cortex and progresses to hippocampus. a Immunofluorescence staining of 2-month-old mouse brains. Cortical neurons were stained with NC4 antibody (red) in TG mice but not in WT littermate controls. Sections were counterstained with DAPI to identify nuclei (blue). b Immunofluorescence staining of 6-month-old mouse brains. Cortex, CA1, and DG were stained with NC4 antibody (red) in TG mice; the extracellular secreted form of COL25A1 was also detected in the DG. WT littermates showed no staining. c Immunohistochemical staining of 1-year-old mouse brains. NC4 staining was prominent in cortex, CA1, DG, reticular thalamic nuclei (RT), globus pallidus (GP), and subiculum in TG but not in WT control mice. Both precursor and secreted forms of COL25A1 were detected
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Fig1: COL25A1 expression in TG mice begins in cortex and progresses to hippocampus. a Immunofluorescence staining of 2-month-old mouse brains. Cortical neurons were stained with NC4 antibody (red) in TG mice but not in WT littermate controls. Sections were counterstained with DAPI to identify nuclei (blue). b Immunofluorescence staining of 6-month-old mouse brains. Cortex, CA1, and DG were stained with NC4 antibody (red) in TG mice; the extracellular secreted form of COL25A1 was also detected in the DG. WT littermates showed no staining. c Immunohistochemical staining of 1-year-old mouse brains. NC4 staining was prominent in cortex, CA1, DG, reticular thalamic nuclei (RT), globus pallidus (GP), and subiculum in TG but not in WT control mice. Both precursor and secreted forms of COL25A1 were detected

Mentions: TG mice were generated with a human COL25A1 cDNA driven by the murine Thy1.2 promoter, and two independent lines (861 and 797) were maintained. TG human COL25A1 and endogenous mouse Col25a1 were distinguished immunohistochemically with a human-specific antibody against NC4 (Fig. 1). In 2-month-old TG mice, cortical neurons stained positively for NC4 primarily in cell membranes, suggesting that the detected protein was the precursor form of COL25A1 (Fig. 1a). In 6-month-old TG mice, NC4 staining of the COL25A1 precursor was strong in the cortex, CA1 pyramidal neurons, dentate gyrus (DG), granule neurons, and thalamic cells (Fig. 1b). Secreted forms of COL25A1 were detected in extracellular matrix (ECM) of cortex and DG and formed fibrillar ECM deposits in 6-month-old mice. In 1-year-old mice, both forms of COL25A1 were strongly detected in whole brain, including cortex, hippocampus, and thalamus (Fig. 1c). These results suggest that the murine Thy1.2 expression cassette drives COL25A1 expression in a temporal–spatial pattern beginning in the cortex and progressing to the hippocampus.Fig. 1


COL25A1 triggers and promotes Alzheimer's disease-like pathology in vivo.

Tong Y, Xu Y, Scearce-Levie K, Ptácek LJ, Fu YH - Neurogenetics (2009)

COL25A1 expression in TG mice begins in cortex and progresses to hippocampus. a Immunofluorescence staining of 2-month-old mouse brains. Cortical neurons were stained with NC4 antibody (red) in TG mice but not in WT littermate controls. Sections were counterstained with DAPI to identify nuclei (blue). b Immunofluorescence staining of 6-month-old mouse brains. Cortex, CA1, and DG were stained with NC4 antibody (red) in TG mice; the extracellular secreted form of COL25A1 was also detected in the DG. WT littermates showed no staining. c Immunohistochemical staining of 1-year-old mouse brains. NC4 staining was prominent in cortex, CA1, DG, reticular thalamic nuclei (RT), globus pallidus (GP), and subiculum in TG but not in WT control mice. Both precursor and secreted forms of COL25A1 were detected
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2807601&req=5

Fig1: COL25A1 expression in TG mice begins in cortex and progresses to hippocampus. a Immunofluorescence staining of 2-month-old mouse brains. Cortical neurons were stained with NC4 antibody (red) in TG mice but not in WT littermate controls. Sections were counterstained with DAPI to identify nuclei (blue). b Immunofluorescence staining of 6-month-old mouse brains. Cortex, CA1, and DG were stained with NC4 antibody (red) in TG mice; the extracellular secreted form of COL25A1 was also detected in the DG. WT littermates showed no staining. c Immunohistochemical staining of 1-year-old mouse brains. NC4 staining was prominent in cortex, CA1, DG, reticular thalamic nuclei (RT), globus pallidus (GP), and subiculum in TG but not in WT control mice. Both precursor and secreted forms of COL25A1 were detected
Mentions: TG mice were generated with a human COL25A1 cDNA driven by the murine Thy1.2 promoter, and two independent lines (861 and 797) were maintained. TG human COL25A1 and endogenous mouse Col25a1 were distinguished immunohistochemically with a human-specific antibody against NC4 (Fig. 1). In 2-month-old TG mice, cortical neurons stained positively for NC4 primarily in cell membranes, suggesting that the detected protein was the precursor form of COL25A1 (Fig. 1a). In 6-month-old TG mice, NC4 staining of the COL25A1 precursor was strong in the cortex, CA1 pyramidal neurons, dentate gyrus (DG), granule neurons, and thalamic cells (Fig. 1b). Secreted forms of COL25A1 were detected in extracellular matrix (ECM) of cortex and DG and formed fibrillar ECM deposits in 6-month-old mice. In 1-year-old mice, both forms of COL25A1 were strongly detected in whole brain, including cortex, hippocampus, and thalamus (Fig. 1c). These results suggest that the murine Thy1.2 expression cassette drives COL25A1 expression in a temporal–spatial pattern beginning in the cortex and progressing to the hippocampus.Fig. 1

Bottom Line: COL25A1 alleles have been associated with increased risk for AD in a Swedish population.These findings demonstrate that COL25A1 leads to AD-like pathology in vivo.Modulation of COL25A1 function may represent an alternative therapeutic intervention for AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of California San Francisco, 1550 Fourth Street, Rock Hall Rm548, San Francisco, CA, 94158, USA.

ABSTRACT
Collagen XXV alpha 1 (COL25A1) is a collagenous type II transmembrane protein purified from senile plaques of Alzheimer's disease (AD) brains. COL25A1 alleles have been associated with increased risk for AD in a Swedish population. COL25A1 is specifically expressed in neurons and binds to aggregated Abeta in vitro. However, its contribution to the pathogenesis of AD and in vivo function are unknown. Here, we report that over-expression of COL25A1 in transgenic mice increases p35/p25 and beta-site APP-cleaving enzyme 1 (BACE1) levels, facilitates intracellular aggregation and extracellular matrix deposits of Abeta, and causes synaptophysin loss and astrocyte activation. COL25A1 mice displayed reduced anxiety-like behavior in elevated plus maze and open field tests and significantly slower swimming speed in Morris water maze. In stable cell lines, motifs in noncollagenous domains of COL25A1 were important for the induction of BACE1 expression. These findings demonstrate that COL25A1 leads to AD-like pathology in vivo. Modulation of COL25A1 function may represent an alternative therapeutic intervention for AD.

Show MeSH
Related in: MedlinePlus