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Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease.

Yao J, Ho D, Calingasan NY, Pipalia NH, Lin MT, Beal MF - J. Exp. Med. (2012)

Bottom Line: There is extensive evidence that cholesterol and membrane lipids play a key role in Alzheimer disease (AD) pathogenesis.Cyclodextrins (CD) are cyclic oligosaccharide compounds widely used to bind cholesterol.HP-β-CD dramatically lowered the levels of Aβ42 in SwN2a cells, and the effects were persistent for 24 h after withdrawal. 4 mo of subcutaneous HP-β-CD administration significantly improved spatial learning and memory deficits in Tg19959 mice, diminished Aβ plaque deposition, and reduced tau immunoreactive dystrophic neurites.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA. jiy2006@med.cornell.edu

ABSTRACT
There is extensive evidence that cholesterol and membrane lipids play a key role in Alzheimer disease (AD) pathogenesis. Cyclodextrins (CD) are cyclic oligosaccharide compounds widely used to bind cholesterol. Because CD exerts significant beneficial effects in Niemann-Pick type C disease, which shares neuropathological features with AD, we examined the effects of hydroxypropyl-β-CD (HP-β-CD) in cell and mouse models of AD. Cell membrane cholesterol accumulation was detected in N2a cells overexpressing Swedish mutant APP (SwN2a), and the level of membrane cholesterol was reduced by HP-β-CD treatment. HP-β-CD dramatically lowered the levels of Aβ42 in SwN2a cells, and the effects were persistent for 24 h after withdrawal. 4 mo of subcutaneous HP-β-CD administration significantly improved spatial learning and memory deficits in Tg19959 mice, diminished Aβ plaque deposition, and reduced tau immunoreactive dystrophic neurites. HP-β-CD lowered levels of Aβ42 in part by reducing β cleavage of the APP protein, and it also up-regulated the expression of genes involved in cholesterol transport and Aβ clearance. This is the first study to show neuroprotective effects of HP-β-CD in a transgenic mouse model of AD, both by reducing Aβ production and enhancing clearance mechanisms, which suggests a novel therapeutic strategy for AD.

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HP-β-CD treatment prominently reduces the levels of Aβ in brain extracts from Tg19959 mice. (A) Representative image of Western blots of Aβ, detected with 6E10 antibody and normalized to tubulin. *, P < 0.05. (B) Levels of Aβ42 and Aβ40 examined by ELISA. *, P < 0.05. (C) Western blots of β-CTFs (left gel) using 6E10 antibody. Short exposure image shows full-length APP. The levels of β-CTFs were normalized to tubulin. (D) The same membrane stripped and re-blotted with an APP C-terminal antibody to show α- and β-CTFs. n = 4 (Tg); n = 7 (Tg-CD). All results were analyzed from two separate animal studies.
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fig5: HP-β-CD treatment prominently reduces the levels of Aβ in brain extracts from Tg19959 mice. (A) Representative image of Western blots of Aβ, detected with 6E10 antibody and normalized to tubulin. *, P < 0.05. (B) Levels of Aβ42 and Aβ40 examined by ELISA. *, P < 0.05. (C) Western blots of β-CTFs (left gel) using 6E10 antibody. Short exposure image shows full-length APP. The levels of β-CTFs were normalized to tubulin. (D) The same membrane stripped and re-blotted with an APP C-terminal antibody to show α- and β-CTFs. n = 4 (Tg); n = 7 (Tg-CD). All results were analyzed from two separate animal studies.

Mentions: HP-β-CD decreased Aβ levels and β-secretase cleavage of APP in SwN2a cells. To investigate Aβ levels and APP processing in vivo, protein was extracted from brains of Tg19959 mice treated with and without HP-β-CD and subjected to Western blotting. To detect Aβ, the 6E10 antibody was used (Fig. 5 A). Tubulin was used as a loading control. Levels of Aβ were significantly reduced in the brains of Tg19959 mice treated with HP-β-CD (P < 0.05). The same extract was also analyzed quantitatively for Aβ42 and Aβ40 by ELISA. Levels of both Aβ42 and Aβ40 per brain weight were significantly reduced in Tg19959 mice treated with HP-β-CD (Fig. 5 B; P < 0.05). We also examined the levels of APP CTFs, using the 6E10 and APP C-terminal antibodies (Fig. 5, C and D). Both antibodies recognize β-CTFs, but only the APP C-terminal antibody recognizes α-CTFs. As shown in Fig. 5 C, HP-β-CD treatment did not affect full-length APP (short exposure time with 6E10), but it significantly lowered the level of β-CTFs (P < 0.05). The levels of α-CTFs, normalized to tubulin, were not changed significantly by HP-β-CD (Fig. 5 D). Thus, HP-β-CD decreased brain Aβ levels in vivo, at least in part by reducing amyloidogenic processing of APP.


Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease.

Yao J, Ho D, Calingasan NY, Pipalia NH, Lin MT, Beal MF - J. Exp. Med. (2012)

HP-β-CD treatment prominently reduces the levels of Aβ in brain extracts from Tg19959 mice. (A) Representative image of Western blots of Aβ, detected with 6E10 antibody and normalized to tubulin. *, P < 0.05. (B) Levels of Aβ42 and Aβ40 examined by ELISA. *, P < 0.05. (C) Western blots of β-CTFs (left gel) using 6E10 antibody. Short exposure image shows full-length APP. The levels of β-CTFs were normalized to tubulin. (D) The same membrane stripped and re-blotted with an APP C-terminal antibody to show α- and β-CTFs. n = 4 (Tg); n = 7 (Tg-CD). All results were analyzed from two separate animal studies.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3526350&req=5

fig5: HP-β-CD treatment prominently reduces the levels of Aβ in brain extracts from Tg19959 mice. (A) Representative image of Western blots of Aβ, detected with 6E10 antibody and normalized to tubulin. *, P < 0.05. (B) Levels of Aβ42 and Aβ40 examined by ELISA. *, P < 0.05. (C) Western blots of β-CTFs (left gel) using 6E10 antibody. Short exposure image shows full-length APP. The levels of β-CTFs were normalized to tubulin. (D) The same membrane stripped and re-blotted with an APP C-terminal antibody to show α- and β-CTFs. n = 4 (Tg); n = 7 (Tg-CD). All results were analyzed from two separate animal studies.
Mentions: HP-β-CD decreased Aβ levels and β-secretase cleavage of APP in SwN2a cells. To investigate Aβ levels and APP processing in vivo, protein was extracted from brains of Tg19959 mice treated with and without HP-β-CD and subjected to Western blotting. To detect Aβ, the 6E10 antibody was used (Fig. 5 A). Tubulin was used as a loading control. Levels of Aβ were significantly reduced in the brains of Tg19959 mice treated with HP-β-CD (P < 0.05). The same extract was also analyzed quantitatively for Aβ42 and Aβ40 by ELISA. Levels of both Aβ42 and Aβ40 per brain weight were significantly reduced in Tg19959 mice treated with HP-β-CD (Fig. 5 B; P < 0.05). We also examined the levels of APP CTFs, using the 6E10 and APP C-terminal antibodies (Fig. 5, C and D). Both antibodies recognize β-CTFs, but only the APP C-terminal antibody recognizes α-CTFs. As shown in Fig. 5 C, HP-β-CD treatment did not affect full-length APP (short exposure time with 6E10), but it significantly lowered the level of β-CTFs (P < 0.05). The levels of α-CTFs, normalized to tubulin, were not changed significantly by HP-β-CD (Fig. 5 D). Thus, HP-β-CD decreased brain Aβ levels in vivo, at least in part by reducing amyloidogenic processing of APP.

Bottom Line: There is extensive evidence that cholesterol and membrane lipids play a key role in Alzheimer disease (AD) pathogenesis.Cyclodextrins (CD) are cyclic oligosaccharide compounds widely used to bind cholesterol.HP-β-CD dramatically lowered the levels of Aβ42 in SwN2a cells, and the effects were persistent for 24 h after withdrawal. 4 mo of subcutaneous HP-β-CD administration significantly improved spatial learning and memory deficits in Tg19959 mice, diminished Aβ plaque deposition, and reduced tau immunoreactive dystrophic neurites.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA. jiy2006@med.cornell.edu

ABSTRACT
There is extensive evidence that cholesterol and membrane lipids play a key role in Alzheimer disease (AD) pathogenesis. Cyclodextrins (CD) are cyclic oligosaccharide compounds widely used to bind cholesterol. Because CD exerts significant beneficial effects in Niemann-Pick type C disease, which shares neuropathological features with AD, we examined the effects of hydroxypropyl-β-CD (HP-β-CD) in cell and mouse models of AD. Cell membrane cholesterol accumulation was detected in N2a cells overexpressing Swedish mutant APP (SwN2a), and the level of membrane cholesterol was reduced by HP-β-CD treatment. HP-β-CD dramatically lowered the levels of Aβ42 in SwN2a cells, and the effects were persistent for 24 h after withdrawal. 4 mo of subcutaneous HP-β-CD administration significantly improved spatial learning and memory deficits in Tg19959 mice, diminished Aβ plaque deposition, and reduced tau immunoreactive dystrophic neurites. HP-β-CD lowered levels of Aβ42 in part by reducing β cleavage of the APP protein, and it also up-regulated the expression of genes involved in cholesterol transport and Aβ clearance. This is the first study to show neuroprotective effects of HP-β-CD in a transgenic mouse model of AD, both by reducing Aβ production and enhancing clearance mechanisms, which suggests a novel therapeutic strategy for AD.

Show MeSH
Related in: MedlinePlus