Peripheral treatment with enoxaparin exacerbates amyloid plaque pathology in Tg2576 mice
Our previous studies and those of other groups (Snow et al., 1988; Kisilevsky et al., 1995; Dudas et al., 2002; Scholefield et al., 2003; Bergamaschini et al., 2004) have shown that glycosaminoglycans (GAGs) or GAG analogues may have potential for the treatment of AD. Enoxaparin (ENO) is a low‐molecular‐weight heparin currently used as an anticoagulant and antithrombotic drug (Weitz, 1997). Studies have shown that treatment of primary cortical cells derived from Tg2576 mice with heparin or ENO could lower Aβ secretion (Cui et al., 2011). Although heparin can bind directly to BACE1 and modulate its activity (Scholefield et al., 2003; Beckman et al., 2006; Klaver et al., 2010), the decreased secretion of Aβ in primary cortical cells was due to a reduction in BACE1 rather than to direct inhibition of the enzyme (Cui et al., 2011).
Peripheral administration of ENO was reported to reduce Aβ level and amyloid deposits in the brain of APP23 mice (Bergamaschini et al., 2004). Timmer and colleagues (2010) further demonstrate that ENO improves cognition in APPswe/PS1dE9 mice and reduces Aβ production at the early stage of Aβ accumulation but increases Aβ levels at the late stage of the disease. These in vivo studies suggest that ENO may offer a promising approach for the treatment of AD. However, the mechanisms underlying the different effects of ENO on Aβ production are still unclear. Based on our previous results, it seemed possible that treatment with ENO might suppress APP processing by downregulating the level of BACE1, leading to a reduction in Aβ and amyloid plaque load.
The aim of this study was to confirm whether ENO treatment could lower brain amyloid plaque load and to investigate the mechanism by which this might occur by examining the level of APP processing products, APP cleavage enzymes (BACE1 and ADAM10), and amyloid plaque load in the brain of ENO‐treated Tg2576 mice. A major advantage of Tg2576 mice is that APP and APP proteolytic products can be easily detected by Western blotting. We report that, contrary to previous work, ENO treatment significantly increases the Aβ42/Aβ40 ratio in the cerebral cortex and increases the amyloid plaque load in both the cortex and the hippocampus but has no effects on β‐secretase processing of APP.