VOL. 2, No. 2, January 2005

R. J. Castellani, et al. [2005] Med Hypotheses Res 2: 393-400.

Involvement of Complex Carbohydrate Chemistry in
Alzheimer Disease

Rudy J. Castellani*, David A. DeWitt, George Perry and Mark A.

Department of Physiology (Neuropathology), Michigan State University, East Lansing,
Michigan (R.J.C.); Department of Biology and Chemistry, Liberty University, Lynchburg,
Virginia (D.A.D.); and Institute of Pathology, Case Western Reserve University, Cleveland,
Ohio (G.P., M.A.S.), USA

Abstract.  The cardinal feature of Alzheimer disease is the extracellular deposition of
proteinaceous amyloid-β fibrils as senile plaques. Amyloid-β plays an essential role in disease
diagnosis and is also thought by many to be a key mediator of disease pathogenesis. As such,
there are tremendous efforts underway to understand mechanisms of amyloid deposition. In
this context, it is notable that the actual term amyloid, represents a historical misnomer
(being derived from amylose, i.e., starch) and since this realization, the contribution of
carbohydrates in disease pathogenesis has largely been ignored. However, recently, two
emerging lines of evidence indicate not only that the interaction of carbohydrates with
amyloid is a key event in disease pathogenesis but also that therapeutic efforts targeted
towards such pathways may prove therapeutically efficacious. First, just over a decade ago,
we and others discovered that oxidative glycation, similar if not identical to that found in
diabetes, was an early and chronic contributor to the disease. Second, we very recently found
evidence for the presence of chitin-like polysaccharides in association with amyloid deposits
in the diseased brain. Both carbohydrate-associated changes likely contribute to the
physiochemical properties of amyloid (and other disease-related proteins such as tau) and, as
such, to the insolubility and protease-resistance of amyloid. In fact, taken together, the
findings indicate an emerging and important role for carbohydrates in the pathogenesis of
Alzheimer disease.

*Address all correspondence to: Dr. Rudy J. Castellani, B218 Clinical Center, 138 Service
Road, East Lansing, MI 48824, USA.  Phone: 517-432-6459. Fax: 517-432-3056.

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