New Advances in Alzheimer's Disease: From Biology to Therapy

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that results in the loss of memory and cognitive function, and eventually dementia. AD is the most common cause of dementia and the eighth leading cause of death. Increasing age is the greatest risk factor for AD. Under the age of 65 the disease is rare, but it increases dramatically: the disease affects one in 10 individuals over age of 65 and nearly half the population over age of 85. Some 4.5 million individuals in the United States have Alzheimer's disease [1, 2]. Scientists estimate that as the population continues to age and baby boomers reach retirement age and beyond, this number will triple by the year 2050. With this expected increase in the prevalence of AD there will be an increase in the financial burden caused by this condition. Thus, therapies aimed at the prevention and the treatments of AD are desperately needed. This issue of Current Genomics is dedicated to the most recent advances in AD research, which began 100 years ago when the disease was first described. A key neuropathological event in AD is the cerebral accumulation of an ~4kDa peptide termed A, the principle component of senile plaques. Amyloid plaques are formed by aggregates of amyloid-peptides, 37-43 amino-acid fragments (predominantly A 40 and A 42) derived by serial proteolysis of the amyloid precursor protein (APP) by-and-secretase. APP more commonly undergoes a non-amyloidogenic processing by-secretase that cleaves in the middle of the-amyloid domain [3].-secretase has been identified as a novel membrane-tethered member of the aspartyl proteases, termed BACE [4, 5], while candidate-secretases include ADAM 9, 10 and 17 (TACE, tumor necrosis factor-converting enzyme) [6, 7]. Recent findings have shown that-secretase is a complex of four proteins including presenilin, nicastrin/Aph2, Aph1 and Pen-2 [8]. A central role for A in AD pathogenesis is supported by studies of human genetics and data derived from both in vitro and in vivo models. In this issue of Current Genomics, Dr. Lacor reviews the findings that had led to development of the-amyloid hypothesis, which states that A accumulation is the initial step of a cascade of events starting with dysfunction of synaptic transmission and evolving in the degeneration of neuronal cells. A can exist in a variety of different forms, including monomers, oligomers, protofibrils and fibrils. Dr. Lacor clearly discusses the toxicity of the different A forms focusing on the synaptic toxicity of oligomeric …