Marking the Centennial of Alzheimers First Report of the Disease with a Perspective of Ongoing Research and Future Challenge

Debomoy   K.   Lahiri; Frank   M.   LaFerla

doi:10.2174/156720506779025260

Abstract

Current Alzheimer Research presents the fifth issue of its third volume and this special issue is meant to mark the centennial of Alois Alzheimer s original de-scription of the disease that would come to bear his name. How best can one commemorate this seminal discovery Since the field has become quite diverse and large, it is difficult to accommodate all the fasci-nating areas of Alzheimers disease (AD), nor could we invite contributions from all the respective fields lead-ing scientists within a limited space of the special issue. Instead of adopting the historical approach, we have invited selected leaders in the field to share their work with the readers of the journal in order to capture a glimpse of current research on AD. We review the pro-gress of a sample of cutting-age work in various as-pects of the disorder in terms of mechanism and thera-peutic implication. The articles in this special issue cover a wide range of cellular, molecular and animal-based research, ranging from the rol es of amyloid, tau protein, genetics and oxidative stress to brain imaging on neurobiology and pathogenesis of AD using innova-tive experimental models. AD is the most common form of dementia in the US and most of the world, with rates increasing exponen-tially from age 65. A significant increase in life expec-tancy during the last century has resulted in a large number of people living to old age, and this will cause a quadrupling of AD cases by the middle of the cen-tury. Therefore, a systematic study of the disease is of paramount importance to understand the neurobiology, genetics and environmental risk factors of AD; these studies will lead to development of effective drug tar-gets and therapeutic approaches. The present issue reports fourteen articles discuss-ing the most exciting and relevant topics in the field of AD. The first article is a timely review by Kawas and Corrada (page 411-419) on the ‘90+ Study’ to address some of the unanswered questions about AD and de-mentia in the oldest-old. Since the initial description one hundred years ago by Alzheimer, the disorder is still being mainly characterized by the occurrence of two brain lesions: amyloid plaques and neurofibrillary tangles (NFTs). From that time, onwards, a significant advance has been made in characterization of these lesions and their role in AD pathogenesis, employing different cellular and animal models. For example, amyloid plaques have been shown mostly to comprise amyloid β-peptide (Aβ), whereas NFTs are composed of hyperphosphoryalted tau proteins. However, the pre-cise relationship between Aβ and tau, the two proteins that accumulate within the brain lesions, is just begin-ning to be understood. Two paper s discuss about the production of Aβ , and its proteolytic degradation. Golde et al. present (page 421-430) different aspects of the ‘Aβ Cascade Hypothesis’ of AD, and argue for an array of therapeutic interventions that could target Aβ metabolism. In addition to Aβ production, Leissring emphasizes (page 431-435) the role of Aβ clearance (proteolytic degradation) by Aβ-degrading proteases in AD. The relationship between Aβ and tau proteins is the subject matter of another set of two papers. Blur-ton-Jones and LaFerla discuss (page 437-448) how Aβ accumulation facilitates tau pathology, whereas Mi and Johnson describe (page 449-463) the role of tau phos-phorylation in AD pathogenesis. In addition to neuro-pathological markers, genetic and environmental factors are elucidated. Ryman and Lamb analyze (page 465-473) the implications of genetic modifiers for mouse and human AD research, and responsiveness to environmental or treatment interventions. A detailed molecular analysis by Lahiri et al. (page 475-484) of an important gene, beta secretase (BACE1), reveals poten-tial drug targets within the BACE1 regulatory region. Cruts and colleagues narrate (page 485-491) the dis-covery of novel genetic mutations in frontotempral dementia, and such work represents how far genetic research has progressed in the field of neurodegenera-tion and AD over the years. But genes are not the only culprits as steps can go awry down at the protein level during the disease process. Urbane and colleagues update (page 493-504) on proper protein folding and assembly and their role in AD, which represent an important area of current research. Apart from the characteristic β-amyloid and tau proteins, Tesseur and Wyss-Coray highlight (page 505-513) the role of trophic factors and dysregulation of TGF-β signaling in neurodegeneration. Cell signaling to mitochondria and oxidative stress constitute two other important articles......