Chitin-like Polysaccharides in Alzheimers Disease Brains

Abstract

The role of polysaccharides in the pathogenesis of Alzheimer disease (AD) is unclear. However, in light of studies indicating impaired glucose utilization in AD and increased activation of the hexosamine pathway that is seen with hyperglycemia, in the brains of patients with AD, aberrantly high levels of glucosamine may result in synthesis of glucosamine polymers such as chitin, a highly insoluble polymer of N-acetyl glucosamine, linearized by beta1-4 linkages. To examine this further, we studied brain tissue at autopsy from subjects with sporadic and familial AD using calcofluor histochemistry. Calcofluor excites on exposure to ultraviolet light and exhibits a high affinity for chitin in vivo by interacting with beta1-4 linkages. Amyloid plaques and blood vessels affected by amyloid angiopathy showed bright fluorescence. Moreover, treatment with chitinase, followed by beta-N-acetyl glucosaminidase showed a decrease in calcofluor fluorescence. Since chitin is a highly insoluble molecule and a substrate for glycan-protein interactions, chitin-like polysaccharides within the brain could facilitate nucleation of amyloid proteins in various amyloidoses including AD.

Microglia and Chitotriosidase in Multiple Sclerosis

“…33,34,40,41 In this light, the high Chit expression -as demonstrated also by Di Rosa and collaborators 42 -may have a dual role: it either represents a mere epiphenomenon of a strong macrophagemicroglia activation due to β-amyloid deposition, or reflects a scavenging protective immune activity against potentially pathogenic chitin-like glucosamine polymers. 33 Thus, encouraged by these findings, we performed an immunocytochemistry study in order to explore the presence of chitin-like substances within AD, MS and healthy control (HC) brains. On the one hand, we could confirm the presence of abundant chitin-like substances in the brains of AD patients, which may well relate to the detection of peripheral Chit activity.…”

“…13,14,27,51,57 If β-amyloid has a pathogenic and not only a pathognomonic role in AD, the role of chitin may be that of favouring and accelerating its detrimental deposition. 33 Recently, Castellani and colleagues 34 suggested that chitin-like polysaccharides within the AD brain could provide a scaffolding for β-amyloid deposition and that glucosamine may therefore facilitate the process of amyloidosis. This finding may support the hypothesis that an imbalance between glucosamine polymerisation and degradation in AD favours fibril formation.…”

“…Thus, the different histochemical content of chitin-like substances recently found between MS and AD brain samples may be a reflection of different pathophysiological mechanisms. 33,34,43 The markedly augmented glucose metabolism occurring during inflammation in the MS brain could induce a spontaneous increase of glucosamine-derived chitinlike substances. In this context, the microglia-derived Chit activity 48 could counterbalance the naturally occurring glucosamine aggregation as well as its transformation into detrimental chitin, thus having a protective rather than a detrimental role within the CNS.…”

“…31 However, glucosamine polymers are also the building blocks of chitin and chitosaccharides. 28,[32][33][34] Thus, the markedly augmented glucose metabolism that occurs during inflammation or hypoperfusion within the brain could induce increased formation of chitin-like substances. 33,34 …”

“…Such polymers are suggested to induce the formation of pathogenic amyloid fibrils. 33,34 Based on this original finding, we first conducted an association study of Chit in the plasma of people with AD, 18 analysing Chit activity in AD patients and healthy individuals. Results were unexpectedly interesting and indicated that Chit values in the AD group were significantly higher than those obtained from individuals of comparable age.…”