Abstract
Alzheimer's disease (AD) is a slowly progressive, neurodegenerative disorder of uncertain etiology. According to the amyloid cascade hypothesis, accumulation of non-soluble amyloid β peptides (Aβ) in the Central Nervous System (CNS) is the primary cause initiating a pathogenic cascade leading to the complex multilayered pathology and clinical manifestation of the disease. It is, therefore, not surprising that the search for mechanisms underlying cognitive changes observed in AD has focused exclusively on the brain and Aβ-inducing synaptic and dendritic loss, oxidative stress, and neuronal death. However, since Aβ depositions were found in normal non-demented elderly people and in many other pathological conditions, the amyloid cascade hypothesis was modified to claim that intraneuronal accumulation of soluble Aβ oligomers, rather than monomer or insoluble amyloid fibrils, is the first step of a fatal cascade in AD. Since a characteristic reduction of cerebral perfusion and energy metabolism occurs in patients with AD it is suggested that capillary distortions commonly found in AD brain elicit hemodynamic changes that alter the delivery and transport of essential nutrients, particularly glucose and oxygen to neuronal and glial cells. Another important factor in tissue oxygenation is the ability of erythrocytes (red blood cells, RBC) to transport and deliver oxygen to tissues, which are first of all dependent on the RBC antioxidant and energy metabolism, which finally regulates the oxygen affinity of hemoglobin. In the present review, we consider the possibility that metabolic and antioxidant defense alterations in the circulating erythrocyte population can influence oxygen delivery to the brain, and that these changes might be a primary mechanism triggering the glucose metabolism disturbance resulting in neurobiological changes observed in the AD brain, possibly related to impaired cognitive function. We also discuss the possibility of using erythrocyte biochemical aberrations as potential tools that will help identify a risk factor for AD.
Highlights
Alzheimer’s disease (AD) is a slowly progressing, systemic neurodegenerative disorder of uncertain etiology
We found that activities of all glycolytic, pentose phosphate pathway and 2,3-DPG shunt enzymes, Na+, K+ATPase, as well as NAD/NADH ratio, pyruvate and lactate levels decreased in aging and increased in AD and non-Alzheimer’s dementia (NA) to levels or above levels of the young adult controls (YC) group indicating an increase in red blood cells (RBC) glycolysis and ion fluxes
There is an impressive body of evidence indicating that AD is a systemic metabolic disease (Perry et al, 2003), and it has originated as a vascular disorder with the resultant impairment of the delivery and transport of essential nutrients, glucose and oxygen resulting in an energy metabolic breakdown with the plaques and tangles found in the brain secondary to the effects of the vascular pathology
Summary
Alzheimer’s disease (AD) is a slowly progressing, systemic neurodegenerative disorder of uncertain etiology. These findings suggest that a transient insult, e.g., trauma, ischemia, neuroinflammation, anesthesia, or infectious agents could lead to secondary and persistent brain injuries and that the initial production of Aβ and its precursor, perhaps, are associated with physiological compensatory mechanisms for repair or protection of neurons exposed to significant disturbances in homeostasis (Smith et al, 2000; Lee et al, 2004) These facts are consistent with the numerous data showing that amyloid exhibits trophic and neuroprotective (Whitson et al, 1989; Koo et al, 1993; Singh et al, 1994; Luo et al, 1996), antioxidant (Smith et al, 1998, 2002a; Kontush et al, 2001; Atwood et al, 2002) properties and accumulates in the tissue after impairment of the energy metabolism with non-specific stimulus (Gabuzda et al, 1994; Webster et al, 1998; Velliquette et al, 2005), while under physiological conditions the diurnal fluctuation of brain Aβ levels is strictly regulated (Kang et al, 2009). Any pharmacological intervention, directed at correcting the chronic hypoperfusion state would possibly change the natural course of development of dementing neurodegeneration (Aliev et al, 2003a)
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