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Amyloid plaque formation can be inhibited by an unlikely culprit, according to work by Scholefield et al. on page 97. The group finds that heparan sulfate (HS)〞normally a part of the cell surface and extracellular matrix〞functions in cells to slow the production of the plaque components of Alzheimer's disease.0 w5 z" Y3 I& N1 b6 u% T S
5 r8 n# t$ i: ^Amyloid plaques are aggregates of the amyloid ?-peptide (A?). A? is produced upon intracellular cleavage of the amyloid precursor protein (APP) by the BACE1 ?-secretase and subsequent processing of one of the resulting fragments by -secretase. Plaque aggregation in the extracellular matrix is promoted by HS. Scholefield et al. now show that HS also has an anti-plaque activity: it inhibits BACE1.
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9 o3 w% ?+ X# K$ Q/ R9 @The group finds that HS and BACE1 colocalize at the cell surface and in the Golgi〞both regions that have been suggested as sites of APP cleavage. HS binding to BACE1 inhibited the protease's ability to cleave APP by blocking APP's access to the active site.* \0 i W; i, P2 X6 y4 S- c( Z& @
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The level of inhibition of BACE1 was dependent on various aspects of HS structure, including saccharide length and degree of sulfation. Since HS is widely expressed, basal BACE1 activity may be low unless regulated alteration of HS structural motifs relieves the inhibition. The structural specificity of HS inhibition of BACE1 is also consistent with the fact that HS structures are known to change with age and in Alzheimer's disease–affected individuals.6 q( N$ ]5 w) ^/ h# n
9 q `" F5 c5 y% ~" x" K: p0 [: tIn another article in this issue that addresses BACE1 regulation, Lee et al. (page 83) show that BACE1 cleavage is promoted by phosphorylation of APP. These insights into BACE1 regulation should benefit those trying to design drugs that target its activity. Novel heparan-based drugs could even prevent Alzheimer's in two ways〞they might be designed both to inhibit BACE1 production of A? and to interfere with HS promotion of A? aggregation.(Cleavage of APP by BACE1 (red) is preven) |
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发表于 2009-3-6 00:37
发表于 2026-10-12 09:19
