Common threads in neurodegenerative disorders of aging

Abstract

Alzheimer’s & Dementia 2 (2006) 322–326 Meeting Report Common threads in neurodegenerative disorders of aging M. Flint Beal, Ella Bossy-Wetzel, Steven Finkbeiner, Gary Fiskum, Benoit Giasson, Carl Johnson, Zaven S. Khachaturian, Virginia M.-Y. Lee, David Nicholls, Hemachandra Reddy, Ian Reynolds, David B. Teplow, Leon J. Thal, John Q. Trojanowski, Dominic M. Walsh, Ronald Wetzel, Nancy S. Wexler, Anne B. Young, and Lisa Bain, reporter * 40 Savits Drive, Elverson, PA 19520, USA 1. Introduction 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 authori- ties 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 dis- eases 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 dys- function? 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 objec- tive of both organizations, that is, improving the lives of patients and families affected by these diseases, participants *Corresponding author. Tel.: 484-769-5486. E-mail address: lbain@nasw.org in the scientific discussions were joined by a woman with AD and her husband. The couple spoke frankly and re- sponded 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 fo- cused 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. 2. Mitochondrial dysfunction in neurodegenerative disease The evidence that mitochondrial dysfunction and oxida- tive damage play a central role in both aging and neurode- generative diseases is strong [1]. Several studies have dem- onstrated 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 cyto- chrome oxidase activity seen in both AD brain tissue and platelets from AD patients. Reduced levels of pyruvate and ␣ -ketoglutarate dehydrogenases are also seen. In transgenic mouse models of AD, oxidative damage precedes deposi- tion of ␤ -amyloid (A ␤ ), and administration of antioxidants significantly reduces A ␤ production and A ␤ plaque depo- sition. Soluble A ␤ is seen in mitochondria as well as else- where in neurons, and amyloid precursor protein (APP) is seen in association with the outer mitochondrial membrane. 1552-5260/06/$ – see front matter © 2006 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2006.08.008