The Erythrocytic Hypothesis of Brain Energy Crisis in Sporadic Alzheimer Disease: Possible Consequences and Supporting Evidence

Abstract

Alzheimer’s disease (AD) is a fatal form of dementia of unknown etiology. Although amyloid plaque accumulation in the brain has been the subject of intensive research in disease pathogenesis and anti-amyloid drug development; the continued failures of the clinical trials suggest that amyloids are not a key cause of AD and new approaches to AD investigation and treatment are needed. We propose a new hypothesis of AD development based on metabolic abnormalities in circulating red blood cells (RBCs) that slow down oxygen release from RBCs into brain tissue which in turn leads to hypoxia-induced brain energy crisis; loss of neurons; and progressive atrophy preceding cognitive dysfunction. This review summarizes current evidence for the erythrocytic hypothesis of AD development and provides new insights into the causes of neurodegeneration offering an innovative way to diagnose and treat this systemic disease.

Characterization of microtubule-associated protein tau isoforms and Alzheimer’s disease-like pathology in normal sheep (Ovis aries): relevance to their potential as a model of Alzheimer’s disease

“…Vascular Aβ deposition was detected throughout the brains of 1–2 and > 5-year-old sheep. The presence of vascular Aβ labelling in the absence of parenchymal Aβ deposition is particularly interesting as it has been hypothesised that both red blood cell and cerebral vascular damage may be key processes that contribute to the development of Aβ plaques [ 53 , 83 ]. It is not clear whether these processes lead to increased parenchymal Aβ deposition due to cellular hypometabolism or increase the influx of Aβ enriched proteins from blood derived cells.…”

“…It is not clear whether these processes lead to increased parenchymal Aβ deposition due to cellular hypometabolism or increase the influx of Aβ enriched proteins from blood derived cells. However, it has been suggested that CAA may represent an intermediate stage in the process of Aβ plaque formation [ 25 , 42 , 53 , 89 ].…”

Is NMDA-Receptor-Mediated Oxidative Stress in Mitochondria of Peripheral Tissues the Essential Factor in the Pathogenesis of Hepatic Encephalopathy?

“…We believe that careful examination and reversal of ammonia-related metabolic/energetic changes in erythrocytes modulating hemoglobin oxygen affinity will undoubtedly stimulate new directions in research and help identify additional risk factors for poor prognosis related to tissue hypoperfusion and multiple organ hypoxia [104][105][106][107] in patients with liver failure and, especially, in elderly patients with age-related erythrocyte metabolic disorders [108].…”

Characterization of microtubule associated protein tau isoforms and Alzheimer’s disease-like pathology in normal sheep (Ovis aries) - relevance to their potential as a model of Alzheimer’s disease.

“…It is not clear whether these processes lead to increased parenchymal Aβ deposition due to cellular hypometabolism or increase the in ux of Aβ enriched proteins from blood derived cells. However, it has been suggested that CAA may represent an intermediate stage in the process of Aβ plaque formation[24,39,50, 82].…”

“…Our data support earlier ndings of AD-like pathology in sheep[60, 67].Vascular Aβ deposition was detected throughout the brains of 1-2 and > 5 year-old sheep. The presence of vascular Aβ labelling in the absence of parenchymal Aβ deposition is particularly interesting as it has been hypothesised that both red blood cell and cerebral vascular damage may be key processes that contribute to the development of Aβ plaques[50, 76]. It is not clear whether these processes lead to increased parenchymal Aβ deposition due to cellular hypometabolism or increase the in ux of Aβ enriched proteins from blood derived cells.…”