Accumulation of high-molecular-weight amylose in Alzheimer's disease brains

Although most of the glucose metabolized in the brain is taken up from the blood, glucose derived from glycogen stores is increasingly implicated in both normal brain function and injury repair. An impaired glucose metabolism is one of the features of Alzheimer's disease (AD) entailing a reduction in glucose transporters and the uptake of glucose as well as alterations in the specific activity of glycolytic enzymes. Here we report that AD brains accumulate amylose, the unbranched alpha(1,4)-linked glucose polymer that is resistant to degradation by glycolytic enzymes. Neutral polysaccharides harvested from postmortem brains were purified with hydrazinolysis, ion exchange, and sizing chromatography and subjected to NMR spectroscopy, GC, GC-MS, and methylation analysis. Five percent of the polysaccharides (50 mug [0.3 mumol]/g wet weight brain tissue) consisted of amylose with molecular weights exceeding 600,000 Da. There is no evidence for 1,6-branching, indicating that the polymer is not a form of high-molecular-weight glycogen. By GC analysis, the glucose content of the AD brains was almost three times greater than that of the age-matched control brains. A synthesis of amylose in AD brains at the expense of glycogen would compromise glucose metabolism and enhance neural degeneration.