Researchers recently reported evidence for some of the complex, toxic halo of biochemistry that surrounds amyloid-β to be capable of causing mitochondrial dysfunction. It is the certainly the case that there is plenty of evidence for mitochondrial dysfunction to be very relevant to age-related neurodegenerative conditions such as Alzheimer's disease. The hundreds of mitochondria found in every cell act as power plants, and the brain is an energy-hungry organ. In most research, however, the direction of causation is that declining and disrupted mitochondrial function causes amyloid-β accumulation and the other manifestations of Alzheimer's disease. Causation can be a two-way street, however. That aging and age-related diseases accelerate as they progress indicates the presence of feedback loops, in which dysfunction A causes dysfunction B, while dysfunction B makes dysfunction A worse. It isn't unreasonable to expect that sort of connection between many of the mechanisms of neurodegeneration, especially in the later stages.
Two pathological hallmarks are observed in Alzheimer's disease (AD) brains at autopsy: intracellular neurofibrillary tangles and extracellular senile plaques, which tend to occur in the neocortex, hippocampus, and other subcortical regions crucial for cognitive function. These observations have led to a dominant theory of Alzheimer's causality, known as the amyloid hypothesis. The theory points to accumulations of the sticky protein substance amyloid-β as the critical factor initiating the chain of events leading to development of Alzheimer's disease. While the amyloid hypothesis continues to exert a considerable hold on the field, an increasing consensus among researchers is moving away from the idea of amyloid-β accumulation as the primary event that sets the disease in motion.
In a new study, researchers examined the effects of the disease on the functioning of mitochondria - structures performing a variety of essential tasks, including supplying cells with energy. The new research reveals that a highly toxic form of amyloid-β protein - known as oligomeric amyloid-β (OAβ) - disrupts the normal functioning of mitochondria. The result is a fateful cascade of events that appears early in the development of AD - decades before the onset of clinical symptoms.
The most promising finding in the new study is that human neuronal cells can be protected from OAβ-induced deterioration of their mitochondria when they are pre-treated with a custom-designed compound, suggesting an exciting avenue for future drug targeting. "Mitochondria are the major source of energy in brain cells and deficiencies in energy metabolism have been shown to be one of the earliest events in Alzheimer's disease pathobiology. This study reinforces the toxicity of oligomeric amyloid-β on neuronal mitochondria and stresses the importance for protective compounds to protect the mitochondria from oligomeric amyloid-β toxicity."
In the new study, cells known as pyramidal neurons, extracted from the hippocampus of patients who died of Alzheimer's, display a marked reduction in the expression of a suite of mitochondrial genes, pointing to their degradation by OAβ. The reduction of mitochondrial gene expression was also seen when cells belonging to a human neuroblastoma cell line were exposed to OAβ. The authors stress that not all types of nervous system cells are implicated in the mitochondrial dysfunction brought on by exposure to OAβ. Hippocampal astrocyte and microglia cells taken from the same AD-afflicted brains did not display reduced mitochondrial function.
One problem with the amyloid theory of Alzheimer's disease is its inconsistency. Researchers have reported that some elderly patients, bearing heavy burdens of amyloid plaque in their brains, lack any measurable cognitive deficit, while other patients showing little to no amyloid buildup nevertheless display severe Alzheimer's-like dementia. These facts have led researchers to seek other processes occurring at the earliest stages, which may kick the disease into gear. One of the most promising avenues of new research is the mitochondrial cascade hypothesis, which places these energy-delivering powerhouses of the cell at the center of the action. The hypothesis suggests that mitochondrial function, which declines as a natural feature of aging, may be further impaired in the presence of amyloid-β, in particular, OAβ. The fact that severe metabolic deficit appears as a prominent feature of AD further implicates energy-delivering mitochondria as likely culprits in the early disease process.