Inherent Abnormalities in Energy Metabolism in Alzheimer Disease: Interaction with Cerebrovascular Compromise

Abstract

Alzheimer disease (AD) is a form of the dementia syndrome. AD appears to have a variety of fundamental etiologies that lead to the neuropathological manifestations which define the disease. Patients who are at high risk to develop AD typically show impairments of cerebral metabolic rate in vivo even before they show any evidence of the clinical disease on neuropsychological, electrophysiological, and neuroimaging examinations. Therefore, impairment in energy metabolism in AD can not be attributed to loss of brain substance or to electrophysiological abnormalities. Among the characteristic abnormalities in the AD brain are deficiencies in several enzyme complexes which participate in the mitochondrial oxidation of substrates to yield energy. There include the pyruvate dehydrogenase complex (PDHC), the alpha-ketoglutarate dehydrogenase complex (KGDHC), and Complex IV of the electron transport chain (COX). The deficiency of KGDHC may be due to a mixture of causes including damage by free radicals and perhaps to genetic variation in the DLST gene encoding the core protein of this complex. Inherent impairment of glucose oxidation by the AD brain may reasonably be expected to interact synergistically with an impaired supply of oxygen and glucose to the AD brain, in causing brain damage. These considerations lead to the hypothesis that cerebrovascular compromise and inherent abnormalities in the brain's ability to oxidize substrates can interact to favor the development of AD, in individuals who are genetically predisposed to develop neuritic plaques.

Astrocytes in Alzheimer's Disease

“…196 Furthermore, co-culturing neurons with astrocytes pre-treated with A␤ significantly decreased neuronal survival as compared with co-culturing with naive astrocytes. 196 Analysis of the activity of metabolic enzymes similarly yielded controversial results: both decrease 197,198 and increase 195,199 in the activity of enzymes associated with glucose metabolism have been reported in AD brain preparations. These discrepancies may reflect opposite cell-specific changes in glucose metabolism developing at different stages of AD.…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Previous studies have suggested that a decrease in brain bioenergetics may be a useful biomarker to predict disease decades before symptoms [33][34][35][36]. Decreases in mitochondrial bioenergetics, metabolic enzyme expression and activity, cerebral glucose metabolism, along with increased oxidative stress, Aβ deposits within mitochondria, and expression of ABAD are associated with the prodromal state of AD [34,[37][38][39][40][41][42].…”

Role and Function of Dehydrogenases in CNS and Blood-Brain Barrier Pathophysiology

“…Defective enzyme function(of dehydrogenases) in pathways of energy metabolism such as glycolysis, tricarboxylic acid pathway and electron transport chain have been well studied in AD progression. Defective PDH, KGDHC, cytochrome oxidase along with reduced activity of hexokinase, phosphofructokinase are the major enzymes reported in AD so far (87). In the paragraph below we will be further discuss some of these DHOs and their mechanism of metabolic dysfunction in AD.…”