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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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Behavioral alterations of COL25A1 TG mice. a–c In the elevated plus maze, TG mice spent significantly more time (a) and traveled longer distances (b) in the open arms than WT littermates. They also spent less time (a) and traveled smaller distances (b) in the closed arms. No difference was found between these two groups in the intersection. Total basic and fine movements of TG mice were not different from WT littermates (c). d, e In the open field test, TG mice spent more time exploring the central zone than WT controls, resulting in a higher ratio of central to peripheral activity (d). Total locomotor activity was similar in the two groups (e). f–h In the Morris water maze, the swimming speed of TG mice was significantly slower than that of WT controls in the visible (f) and hidden (g) platform training sessions and in the probe trials (h). TG (n = 13) and WT littermates (n = 22) were used. Values are mean ± SEM; ***p < 0.001, **p < 0.01, *p < 0.05 (ANOVA)
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Fig3: Behavioral alterations of COL25A1 TG mice. a–c In the elevated plus maze, TG mice spent significantly more time (a) and traveled longer distances (b) in the open arms than WT littermates. They also spent less time (a) and traveled smaller distances (b) in the closed arms. No difference was found between these two groups in the intersection. Total basic and fine movements of TG mice were not different from WT littermates (c). d, e In the open field test, TG mice spent more time exploring the central zone than WT controls, resulting in a higher ratio of central to peripheral activity (d). Total locomotor activity was similar in the two groups (e). f–h In the Morris water maze, the swimming speed of TG mice was significantly slower than that of WT controls in the visible (f) and hidden (g) platform training sessions and in the probe trials (h). TG (n = 13) and WT littermates (n = 22) were used. Values are mean ± SEM; ***p < 0.001, **p < 0.01, *p < 0.05 (ANOVA)

Mentions: COL25A1 TG mice were analyzed in three behavioral assays. In the elevated plus maze test, TG mice spent more time and traveled farther in the open arms than the WT controls (Fig. 3a, b), suggesting disinhibition and reduced anxiety. ANOVA revealed that TG mice spent significantly more time in the open arms (95.4 ± 14.0 vs. 39.9 ± 7.7 s, F(1, 33) = 14.5, p = 0.001; 31.8 ± 4.7% vs. 13.3 ± 2.6%, F(1, 33) = 14.5, p = 0.001) and traveled farther (423.0 ± 69.6 cm vs. 170.2 ± 27.3 cm, F(1, 33) = 15.6, p = 0.0004; 26.9 ± 4.1% vs. 11.2 ± 2.1%, F(1, 33) = 14.1, p = 0.001). Conversely, TG mice spent less time than WT mice in the closed arms (153.9 ± 12.4 vs. 206.7 ± 9.2 s, F(1, 33) = 11.9, p = 0.002; 51.3 ± 4.1% vs. 68.9 ± 3.1%, F(1, 33) = 11.9, p = 0.002) and traveled shorter distances (831.5 ± 72.3 vs. 1,091.2 ± 59.7 cm, F(1, 33) = 7.4, p = 0.010; 52.7 ± 3.7% vs. 68.1 ± 2.6%, F(1, 33) = 12.5, p = 0.001). The numbers of basic and fine movements did not differ in the two groups (Fig. 3c).Fig. 3


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

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

Behavioral alterations of COL25A1 TG mice. a–c In the elevated plus maze, TG mice spent significantly more time (a) and traveled longer distances (b) in the open arms than WT littermates. They also spent less time (a) and traveled smaller distances (b) in the closed arms. No difference was found between these two groups in the intersection. Total basic and fine movements of TG mice were not different from WT littermates (c). d, e In the open field test, TG mice spent more time exploring the central zone than WT controls, resulting in a higher ratio of central to peripheral activity (d). Total locomotor activity was similar in the two groups (e). f–h In the Morris water maze, the swimming speed of TG mice was significantly slower than that of WT controls in the visible (f) and hidden (g) platform training sessions and in the probe trials (h). TG (n = 13) and WT littermates (n = 22) were used. Values are mean ± SEM; ***p < 0.001, **p < 0.01, *p < 0.05 (ANOVA)
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Fig3: Behavioral alterations of COL25A1 TG mice. a–c In the elevated plus maze, TG mice spent significantly more time (a) and traveled longer distances (b) in the open arms than WT littermates. They also spent less time (a) and traveled smaller distances (b) in the closed arms. No difference was found between these two groups in the intersection. Total basic and fine movements of TG mice were not different from WT littermates (c). d, e In the open field test, TG mice spent more time exploring the central zone than WT controls, resulting in a higher ratio of central to peripheral activity (d). Total locomotor activity was similar in the two groups (e). f–h In the Morris water maze, the swimming speed of TG mice was significantly slower than that of WT controls in the visible (f) and hidden (g) platform training sessions and in the probe trials (h). TG (n = 13) and WT littermates (n = 22) were used. Values are mean ± SEM; ***p < 0.001, **p < 0.01, *p < 0.05 (ANOVA)
Mentions: COL25A1 TG mice were analyzed in three behavioral assays. In the elevated plus maze test, TG mice spent more time and traveled farther in the open arms than the WT controls (Fig. 3a, b), suggesting disinhibition and reduced anxiety. ANOVA revealed that TG mice spent significantly more time in the open arms (95.4 ± 14.0 vs. 39.9 ± 7.7 s, F(1, 33) = 14.5, p = 0.001; 31.8 ± 4.7% vs. 13.3 ± 2.6%, F(1, 33) = 14.5, p = 0.001) and traveled farther (423.0 ± 69.6 cm vs. 170.2 ± 27.3 cm, F(1, 33) = 15.6, p = 0.0004; 26.9 ± 4.1% vs. 11.2 ± 2.1%, F(1, 33) = 14.1, p = 0.001). Conversely, TG mice spent less time than WT mice in the closed arms (153.9 ± 12.4 vs. 206.7 ± 9.2 s, F(1, 33) = 11.9, p = 0.002; 51.3 ± 4.1% vs. 68.9 ± 3.1%, F(1, 33) = 11.9, p = 0.002) and traveled shorter distances (831.5 ± 72.3 vs. 1,091.2 ± 59.7 cm, F(1, 33) = 7.4, p = 0.010; 52.7 ± 3.7% vs. 68.1 ± 2.6%, F(1, 33) = 12.5, p = 0.001). The numbers of basic and fine movements did not differ in the two groups (Fig. 3c).Fig. 3

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