Common threads in neurodegenerative disorders of aging

摘要

In recognition of the commonalities that exist among many neurodegenerative diseases of aging, 2 foundations devoted to finding cures for Alzheimer's disease (AD) and Huntington's disease (HD) joined forces at a “think tank” that brought together some of the world's leading authorities on human brain diseases, dementia, memory disorders, and aging. Keep Memory Alive, the foundation for the Lou Ruvo Alzheimer's Institute in Las Vegas, Nevada, partnered with the Hereditary Disease Foundation in sponsoring the workshop and in guiding its participants to consider not only the common pathogenic characteristics of these diseases and the challenges presented by those features, but also the common infrastructural and policy issues that must be addressed to accelerate drug discovery for these and other neurodegenerative diseases. The workshop focused on 2 interrelated pathogenic events: aggregation of misfolded proteins and mitochondrial dysfunction. The causes of both AD and HD have been attributed to both of these events, yet their relationship to one another remains unclear, raising 2 key questions: what is the role of mitochondria in causing protein misfolding, and how might misfolded proteins cause mitochondrial dysfunction? Although no consensus emerged on the precise role of these events in the pathogenesis of AD or HD, there was broad agreement that both processes are likely to play important roles and must be more fully investigated in a variety of in vivo, in vitro, and in silico models. Lest the workshop stray too far from the primary objective of both organizations, that is, improving the lives of patients and families affected by these diseases, participants in the scientific discussions were joined by a woman with AD and her husband. The couple spoke frankly and responded to questions from the scientists and clinicians in attendance about how the memory loss associated with AD has affected her day-to-day functioning and undermined her confidence in the ability to make decisions. They also focused attention on the important role patients and caregivers can play in the search for new treatments and on the need for scientists to pay close attention to patient experiences and what they reveal about pathogenic mechanisms. The evidence that mitochondrial dysfunction and oxidative damage play a central role in both aging and neurodegenerative diseases is strong [1]. Several studies have demonstrated an age-related increase in deletions and point mutations in mitochondrial DNA. Such mutations could lead to impaired energy generation and increased levels of reactive oxygen species (ROS), which could cause cell damage. Animal studies indicate that reducing oxidative stress increases longevity. In AD, longstanding data suggest a defect in the electron transport chain of mitochondria, with a decrease in cytochrome oxidase activity seen in both AD brain tissue and platelets from AD patients. Reduced levels of pyruvate and α-ketoglutarate dehydrogenases are also seen. In transgenic mouse models of AD, oxidative damage precedes deposition of β-amyloid (Aβ), and administration of antioxidants significantly reduces Aβ production and Aβ plaque deposition. Soluble Aβ is seen in mitochondria as well as elsewhere in neurons, and amyloid precursor protein (APP) is seen in association with the outer mitochondrial membrane. In vitro studies have found that the ABAD (Aβ-binding alcohol dehydrogenase) enzyme binds to Aβ and leads to increased production of ROS. ROS, in turn, modulate Aβ production. Blocking ABAD from binding to Aβ in vitro suppresses Aβ-induced apoptosis and free radical generation. In addition, transgenic mouse models of AD show abnormal expression of mitochondrial energy metabolism genes. Despite the evidence suggesting mitochondrial involvement in the AD pathogenic process and a clear link between mitochondrial dysfunction and other neurodegenerative diseases, such as Parkinson's disease (PD), there was no consensus about the i