While present thinking in the research community is leaning towards tau rather than amyloid-β as the primary cause of cell death and dysfunction in later stage Alzheimer's disease, it is still the case that too much amyloid-β is toxic to cells. Researchers here propose a treatment based on suppressing one of the mitochondrial mechanisms of programmed cell death that is triggered by the presence of amyloid-β. This is in many ways a classic example of what I consider to be a problematic focus in medical research: ignoring the root cause damage, the amyloid-β, in favor of tinkering with cellular mechanisms in the hope of improving the dysfunctional, damaged state of cells and tissues.
There are no doubt a hundred places in which one could reasonably try to intervene downstream of the presence of amyloid-β - and a good twenty of those are probably fairly independent of one another, requiring separate research and development project to address. But why build twenty projects when you could build one to achieve the same effect? Target the root causes. Don't mess with the downstream state. I wish that more of that philosophy of development was in evidence in the research community. Sadly it remains a minority viewpoint, barely worked on, judging by what I see in the output of the medical life sciences.
Alzheimer's disease (AD) is the most prevalent type of dementia in the developed world. Despite the enormous efforts made by the scientific community, an effective therapeutic strategy against AD has yet to be developed. The importance of mitochondrial dysfunction in the pathogenesis of AD and other neurodegenerative diseases has been increasingly recognized. A causal relationship has been found between mitochondrial dysfunction and amyloid β (Aβ)-induced neuronal and vascular degeneration. Indeed, mitochondrial pathology, oxidative stress, and energy metabolism impairment are implicated in the pathogenesis of AD, preceding formation of Aβ plaques, cell death, and memory loss.
Mitochondrial-specific therapies are emerging as promising therapeutic tools. It is interesting that mitochondrial therapies have shown beneficial effects in different models of neurodegenerative pathologies, where mitochondrial dysfunction and apoptotic cell death are known to be involved, such as AD, Parkinson's disease, and Huntington's disease.
Carbonic anhydrases (CA) are enzymes involved in the reversible conversion of carbon dioxide and water into bicarbonate and protons. They are present in all the vertebrates, showing different intracellular locations and regulating pH and ion transport. CA-VA and CA-VB have a mitochondrial localization. CA-II, known as cytoplasmic, was also recently shown to be increased in brain mitochondria in aging and neurodegeneration. CA inhibitors (CAIs) are used to treat a variety of disorders. In this study, we examine multiple mitochondrial pathways of amyloid toxicity in neuronal and cerebral endothelial cells (ECs), and evaluate CAIs methazolamide (MTZ) and, for the first time, its analog acetazolamide (ATZ), on specific Aβ-mediated pathways of mitochondrial dysfunction and apoptotic cell death. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Aβ, without affecting metabolic function.
Due to the long-term use of MTZ and ATZ in chronic conditions, the efficacy and the safety of their systemic administration have been widely assessed, making clinical trials for CAIs in AD a concrete possibility. Our novel findings on the mitochondrial effects of MTZ and ATZ against neuronal and vascular amyloid toxicity justify the selection of these drugs as a therapeutic strategy for AD and cerebral amyloid angiopathy.