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Amyloid-β (Aβ) deposition, one of the main hallmarks of Alzheimer's disease (AD), has been linked to glutamatergic dysfunction, i.e., increased stimulation of synaptic glutamate receptors that may ultimately result in neuronal loss. It was our aim to study the effect of Aβ on multiple components of the glutamatergic system, and therefore we assessed the expression of several glutamate-related proteins and amino acids in the TgSwDI mouse model for Aβ pathology. We determined that in TgSwDI mice, levels of several amino acids are altered, in particular that of glycine. Protein changes were only found in 9-month-old TgSwDI mice with extensive Aβ deposits, with the most prominent change an increased expression of vesicular glutamate transporter 1 (vGlut1). Autoradiography experiments demonstrated that, while the number of activated N-methyl-D-aspartic acid (NMDA) receptors was unchanged in TgSwDI mice, binding of the NMDA receptor radioligand [3H]MDL-105,519 to the glycine-binding site of these receptors was increased. Although there are some discrepancies between our results and those found in AD patients, our results suggest that several components of the glutamatergic system might serve as meaningful markers to monitor the progression of AD. [ABSTRACT FROM AUTHOR]

Senile plaques and cerebral amyloid angiopathy in Alzheimer's disease (AD) patients not only consist of the amyloid-β protein (Aβ), but also contain many different Aβ-associated factors, such as heparan sulfate proteoglycans, apolipoproteins, and complement factors. These factors may all influence Aβ deposition, aggregation, and clearance and therefore seem important in the development of human Aβ deposits. To study AD pathology and test new therapeutic agents, many different mouse models have been created. By transgenic expression of the amyloid-β protein precursor, frequently in combination with other transgenes, these animals develop Aβ deposits that morphologically resemble their human counterparts. Whether this resemblance also applies to the presence of Aβ-associated factors is largely unclear. In this review, the co-deposition of factors known to associate with human Aβ deposits is summarized for several different AD mouse models. [ABSTRACT FROM AUTHOR]

Abstract: Enoxaparin (Enox), a low molecular weight heparin, has been shown to lower brain amyloid β (Aβ) load in a mouse model for Alzheimer''s disease. However, the effect of Enox on cognition was not studied. Therefore, we examined the effect of peripheral Enox treatment on cognition and brain Aβ levels in the APPswe/PS1dE9 mouse model by giving injections at an early (starting at 5months of age) and late (starting at 10 and 12months of age) stage of Aβ accumulation for 3 months. Although Enox had no effect on behaviour in the open field at any age, it improved spatial memory in the Morris water maze in 5-, 10- and 12-month-old mice. Furthermore, Enox treatment seemed to decrease guanidine HCl-extracted brain Aβ levels at 5months of age, but significantly increased guanidine HCl-extracted Aβ42 and Aβ40 levels in both 10- and 12-month-old mice. In vitro, Enox increased aggregation of Aβ, even when Aβ was pre-aggregated. In conclusion, Enox treatment, either at an early or a late stage of Aβ accumulation, could improve cognition in APPswe/PS1dE9 mice. However, since Enox treatment at an early stage of Aβ accumulation decreased guanidine HCl-extracted Aβ levels and Enox treatment at a late stage enhanced guanidine HCl-extracted Aβ levels, it seems that Enox influences Aβ deposition differently at different stages of Aβ pathology. In any case, our study suggests that enoxaparin treatment has potential as a therapeutic agent for Alzheimer''s disease. [Copyright &y& Elsevier]

Abstract: Glycosaminoglycans (GAGs), in particular as part of heparan sulfate proteoglycans, are associated with cerebral amyloid angiopathy (CAA). Similarly, GAGs are also associated with the severe CAA found in patients suffering from hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), where the amyloid β (Aβ) peptide contains the Dutch mutation (DAβ1-40). This suggests a role for GAGs in vascular Aβ aggregation. It was the aim of this study to investigate the effect of different GAGs (heparin, chondroitin sulfate, heparan sulfate), the macromolecule dextran sulfate and, using desulfated heparins, the role of GAG sulfate moieties on the in vitro aggregation of CAA-associated DAβ1-40 and on DAβ1-40-induced toxicity of cultured cerebrovascular cells. We also aimed to study the in vivo distribution of various sulfated heparan sulfate GAG epitopes in CAA. Of all GAGs tested, heparin was the strongest inducer of aggregation of DAβ1-40 in the different aggregation assays, with both heparin and heparan sulfate reducing Aβ-induced cellular toxicity. Furthermore, (partial) removal of the sulfate moieties of heparin partially abolished the effects of heparin on aggregation and cellular toxicity, suggesting an essential role for the sulfate moieties in heparin. Finally, we demonstrated the in vivo association of sulfated heparan sulfate (HS) GAGs with CAA. We conclude that sulfate moieties within GAGs, like heparin and HS, have an important role in Aβ aggregation in CAA and in Aβ-mediated toxicity of cerebrovascular cells. [Copyright &y& Elsevier]

Abstract: The major component of senile plaques and vascular amyloid in Alzheimer''s disease (AD) brains is the amyloid β protein (Aβ). Besides Aβ, several other proteins have been identified in these lesions, in particular heparan sulfate proteoglycans (HSPG). However, it is still unclear, what causes the excessive accumulation of HSPG in AD brains. Therefore, we investigated if Aβ may influence production and expression of two major Aβ-associated HSPG species, agrin and glypican-1. When human brain pericytes (HBP) were cultured in the presence of Aβ, protein and mRNA expression of both agrin and glypican-1 were increased and more radioactive sulfate was incorporated in the glycosaminoglycan fraction of Aβ-treated HBP. Furthermore, after Aβ treatment, these HSPG were found in association with the amyloid fibrils attached to the cell membrane, in contrast to the intracellular agrin and glypican-1 staining observed in untreated cells. We conclude that Aβ can modulate the cellular expression of agrin and glypican-1, which may contribute to the accumulation of these HSPG in AD lesions. [Copyright &y& Elsevier]