Affiliations: Department of Psychiatry, University of Toronto and Baycrest Centre, Toronto, ON, Canada
Correspondence:
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Correspondence to: Mortimer Mamelak, Baycrest Centre, 3560 Bathurst Street, Toronto, ON, M5A 2E1, Canada. Tel.: +1 416 236 5650; Fax: +1 416 493 0170; E-mail: m.mamelak@utoronto.ca.
Abstract: A reduction in cerebral glucose utilization is one of the earliest signs of Alzheimer's disease. Although the exact cause of this reduction is not known, gathering evidence suggests that it is part of a complex metabolic adaptation to oxidative stress during which glycolysis and oxidative phosphorylation are turned down, glucose metabolism is shifted to the pentose phosphate pathway to generate antioxidant reducing factors such as nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, and the gamma-aminobutyric acid (GABA) shunt is activated to provide glutamate as an alternate source of energy. In the face of these adaptive metabolic changes, the Alzheimer brain runs short of energy and begins to digest itself. The very early induction of macroautophagy attests to the search for nutrients. In clinical trials, antioxidants alone have not been effectively able to influence the course of the disease as these agents do not meet the energy and nutritional requirements of the brain. Evidence is presented that gammahydroxybutyrate, a natural product of the GABA shunt, can provide the necessary energy, carbon, and antioxidant power and that its use may be able to delay the onset and progress of Alzheimer's disease.
