Alzheimer disease pathology as a host response.
Identification of amyloid-beta and tau as the major protein components of senile plaques and neurofibrillary tangles, respectively, led to an exponential increase in investigations of these proteins and their corresponding metabolic pathways in Alzheimer disease (AD). The presumptions inherent in most studies and in the dogma of the amyloid cascade concept are that these hallmark lesions in AD brains contain molecules that drive the disease process, and that the proteinaceous accumulations are themselves toxic. On the other hand, the lesions of AD are, by definition, end-stage, and their relationship to the clinical disease is inconsistent; this has long been known but, generally, has not been acknowledged until relatively recently. Some recent attempts to address the etiology and pathogenesis of AD discard the pathology and focus on the interplay between invisible toxic intermediates, that is, amyloid-beta oligomers and the synapse. The concept that the hallmark lesions may be nontoxic (something we have long suggested) is slowly gaining acceptance. We favor the interpretation that senile plaques and neurofibrillary tangles represent a host response to an upstream pathophysiologic process, and that the therapeutic targeting of lesions, including toxic intermediates, will succeed only in the event that the host response is directly deleterious. Therefore, renewed efforts aimed at elucidating fundamental age-related processes such as oxidative stress and/or inflammatory mediators are warranted.
Castellani
Rudy J
RJ
Department of Pathology, University of Maryland, Baltimore, Maryland, USA. rcastellani@som.umaryland.edu
Lee
Hyoung-Gon
HG
Zhu
Xiongwei
X
Perry
George
G
Smith
Mark A
MA
D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D016874:Neurofibrillary Tangles / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D058225:Plaque, Amyloid / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016875:tau Proteins