Behavioral analysis of 7-month-old 5XFAD transgenic mice.

<p>5XFAD mice (10 female, 8 male) were analyzed in a series of behavioral tests in comparison to non-transgenic littermates (6 female, 8 male). A significant reduction in body weight (A) of transgenic (white columns) compared to non-transgenic (black columns) mice was observed for both sexes. The grip strength (B) differed between sexes but not between transgenic and non-transgenic mice. Maximum grip strength (black, white columns) and average grip strength (grey, stippled columns) were similar for non-transgenic (black, grey columns) and transgenic mice (white, stippled columns). The rota-rod (C; black control females, grey control males, white transgenic females, dotted transgenic males) did not reveal differences between transgenic and control littermate mice. In the open field (D) transgenic mice (white columns) of both sexes stayed less time in the corners compared to their wild-type littermates (black columns). In the light-dark avoidance paradigm (E, F, G) transgenic mice (white columns) showed less transitions (E), stayed longer time in the light (F), and had a much greater latency to enter the dark compartment (G) both at the first encounter or tested for memory 3 weeks later (grey columns non-transgenic, stippled columns 5XFAD in G). In the O-Maze (H, I) 5XFAD mice (white columns) spend more time (H) and traveled longer distances (I) in the open areas compared to littermate controls (black columns). Fear conditioning (J) did not differ significantly between 5XFAD (white, stippled columns) and control littermate mice (black, grey columns) with respect to freezing in the same context (black, white columns) or when exposed to the tone in a novel environment (grey, stippled columns). Prepulse inhibition of the startle response (K) was not obtained in 5XFAD mice (squares) in contrast to wild-type littermates (diamonds) in both sexes (males open, females filled symbols).</p

Quantification of plaque density after galantamine treatment.

<p>The plaque density in the hippocampus (A) of high dose galantamine treated female (black column, n = 22 sections) and male (white column, n = 47) 5XFAD transgenic mice is significantly reduced in comparison to littermate untreated 5XFAD transgenic mice (female grey column, n = 28; male stippled, n = 50) (***, p<0.0001). The reduction after treatment is even stronger for the entorhinal cortex (B) (treated female black column, n = 27, and male white column, n = 59) (untreated female grey column, n = 45, and male stippled column, n = 59). Astrocyte density and plaque density are strongly correlated in 5XFAD transgenic mice (C) (R² = 0.62; ANOVA F_(1,21) = 34.232; p<0.0001).</p

Progression of plaque formation with age in 5XFAD transgenic mice.

<p>The plaque density in the hippocampus (HC) and entorhinal cortex (EC) of male and female 5XFAD mice at various ages was determined using thioflavin S staining. In males, plaque density increased in both brain areas and reached saturation at 10 months of age. In female mice, plaque accumulation was faster, reached higher levels, and continued to increase after 14 months of age.</p

Water consumption, galantamine uptake, and body weight of 5XFAD-transgenic mice treated with galantamine.

<p>Water consumption (A) of 5XFAD transgenic was similar irrespective of added galantamine (black triangles: water (n = 16); diamonds: high dose (n = 16), squares: low dose (n = 8). Galantamine uptake (B) was calculated from the amount of drinking water consumed for the low dose (squares, 12 then 60 mg/l) and the high dose (diamonds, 36 then 120 mg/l). The body weight (C) of non-transgenic control (black) or 5XFAD (white) mice was not significantly influenced by the treatment and the behavioral tests.</p

Plaque density after galantamine treatment.

<p>Thioflavin S staining of representative coronal brain sections from untreated (A, C, E, G) in comparison to chronically high dose galantamine treated (B, D, F, H) 22-week-old 5XFAD transgenic littermate mice. Fewer plaques are detected in treated animals. Males (A–D) show fewer plaques in comparison to females (E–H), both, in the entorhinal cortex (A, B, E, F) and in the hippocampus (C, D, G, H). Scale bars 500 µm.</p

Brain morphology, amyloid plaque formation, gliosis, and microglial activation in 5XFAD transgenic mice.

<p>Coronal brain sections from 22-week-old wild-type control littermates (A, C, E) and 5XFAD transgenic mice (B, D, F, G, H) were subjected to Nissl staining (A, B) revealing similar brain morphology. Amyloid β immunohistochemistry (C, D) or thioflavin-S staining (E, F) detect numerous amyloid plaques in 5XFAD mice (D, F), whereas wild-type control brains (C, E) are completely devoid of plaques. GFAP immunohistochemistry (activated astrocytes, red in G) or GSA-lectin (activated microglia, red in H) in combination with thioflavin S staining (green in G and H) revealed plaques surrounded by reactive astrocytes and associated with activated microglia in 5XFAD mice. Scale bars: 500 µm (A–F), 250 µm (G, H), and 100 µm (inset in G and H).</p

Behavioral analysis of 5XFAD-transgenic mice after treatment with galantamine.

<p>In the Open Field (A, B) galantamine treatment restored the preference for the corners (A) and the avoidance of the center (B). Non-transgenic mice receiving water (black columns) showed a significantly higher corner preference (**, p = 0.0045) and avoidance of the center (**, p = 0.0048) compared to untreated 5XFAD transgenic mice (white columns). Treatment of 5XFAD transgenic mice with low dose (stippled columns) or high dose (hatched columns) galantamine increased their corner preference and center avoidance in a dose dependent manner. High dose treated transgenic mice spend significantly (**, p = 0.002) more time in the corners compared to untreated transgenic mice or low dose treated mice (*, p = 0.0451). Non-transgenic mice receiving high dose galantamine (grey columns). In the light-dark avoidance paradigm (C, D), high dose galantamine treatment of 5XFAD transgenic mice (hatched columns) reduced the time in the light (C) to untreated non-transgenic (black columns) control levels. In contrast, the number of transitions (D) is even further reduced by galantamine treatment of 5XFAD transgenic mice (*, p<0.005). The magnitude of the startle response (E) was not affected by galantamine treatment of 5XFAD transgenic mice. During fear conditioning (F, G), galantamine increased the context memory (F) and the tone memory (G) of non-transgenic and 5XFAD transgenic mice similarly.</p

Synthesis of 21,23-Selenium- and Tellurium-Substituted 5‑Porphomethenes, 5,10-Porphodimethenes, 5,15-Porphodimethenes, and Porphotrimethenes and Their Interactions with Mercury

The 3+1 condensation of symmetrical 16-Selena/telluratripyrranes with symmetrical selenophene-2,5-diols/tellurophene-2,5-diols in the presence of BF₃-etheratre or BF₃-methanol followed by oxidation with DDQ gave 5,10-porphodimethenes, whereas the process with unsymmetrical selenophene-2,5-diols/tellurophene-2,5-diols gave 5-porphomethenes. In addition, the reaction of unsymmetrical 16-Selena/telluratripyrranes with symmetrical selenophene-2,5-diols/tellurophene-2,5-diols gave the corresponding porphotrimethenes, whereas the process with unsymmetrical selenophene-2,5-diols/tellurophene-2,5-diols gave the 5,15-porphodimethenes. The structures of different products were characterized by IR, ¹H and ¹³C NMR, ¹H–¹H COSY, CHN analysis, and mass spectrometry. The binding of mercury with the calix[4]­phyrins mentioned above had been observed in the decreasing order of porphodimethenes > porphomethenes > porphotrimethenes by UV–vis and ¹H NMR spectroscopy