title: Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta.
abstract: Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-beta-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-beta as the major pathogenic mechanism with the ultimate goal of using amyloid-beta lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on "proteinopathies'' and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition.
authors: Department of Pathology, University of Maryland, Baltimore, MD 21201, USA. rcastellani@som.umaryland.edu
authors: Rudy J
authors: RJ
authors: Castellani
authors: Hyoung-gon
authors: HG
authors: Lee
authors: Sandra L
authors: SL
authors: Siedlak
authors: Akihiko
authors: A
authors: Nunomura
authors: Takaaki
authors: T
authors: Hayashi
authors: Masao
authors: M
authors: Nakamura
authors: Xiongwei
authors: X
authors: Zhu
authors: George
authors: G
authors: Perry
authors: Mark A
authors: MA
authors: Smith
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D016874:Neurofibrillary Tangles / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments