Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10804-9. PubMed.
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University of Heidelberg
In their recent article, Liu et al provided clear evidence that abnormal hyperphospharylation of tau protein may be induced by decreased 0-GlcNAcylation subsequent to a deficient glucose metabolism in Alzheimer disease (AD) brain. Experimentally, the authors damaged brain glucose metabolism by starvation for 48 hours, and this decreased 0-GlcNAcylation resulting in tau-protein hyperphosphorylation. Based on these results, the authors assumed that sporadic AD might be a metabolic brain disorder caused by abnormal cerebral glucose metabolism.
Some supplemental arguments may support this review.
During their processing from the immature to the mature state, proteins undergo modifications including 0-glycosylation and 0-GlcNAcylation. This process takes place in the endoplasmic reticulum (ER)/Golgi apparatus (GA) (1). The function of these intracellular compartments is ensured at a pH of 6 (2), the maintenance of which is ATP-dependent (3).
In sporadic AD brain, ATP formation has been found to be reduced in parallel to the severity of dementia (4) subsequent to decreased glucose comsumption and pertubed glucose metabolism of the brain (5,6). This pathologic condition may reduce neuronal activity, which may diminish the size of the GA (7,8). As a consequence, the processing of proteins in ER/GA may become abnormal, resulting in e.g., hyperphosphorylated tau-protein.
Interestingly, arterial hypoglycemia (as present in starvation) caused an imbalance between normal cerebral oxygen consumption and reduced cerebral glucose utilization (9;10), and this was demonstrated for AD brain, too (5).
Nosologically, AD is not one single disorder. Early onset autosomal dominant familial AD has been documented in 326 families worldwide (11). The amyloid cascade hypothesis serves as the scientific basis of inherited AD. In contrast, millions of people suffer from sporadic AD worldwide, the main risk factor of which is aging. There is no evidence that the amyloid cascade hypothesis is valid for sporadic AD. Instead, there is evidence that a disturbance in the neuronal insulin signal transduction pathway controlling cerebral glucose metabolism may be a central and early pathophysiologic event in sporadic AD (12,13). On the basis of patients‘ data and results from animal studies, the hypothesis was advanced that sporadic AD is the diabetes mellitus II of the brain, and this would include the non-genetic formation of amyloidogenic derivatives and hyperphosphorylated tau-protein. Thus, the findings of Liu et al fit with our hypothesis and support the view that sporadic AD is an age-related metabolic brain disorder (15).
See also:
Eisenberg S, Seltzer HS (1962) Metabolism 11: 1162-1168.
References:
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