Tau phosphorylation in Alzheimer's disease: pathogen or protector?
During the past decade, hypotheses concerning the pathogenesis of most neurodegenerative diseases have been dominated by the notion that the aggregation of specific proteins and subsequent formation of cytoplasmic and extracellular lesions represent a harbinger of neuronal dysfunction and death. As such, in Alzheimer's disease, phosphorylated tau protein, the major component of neurofibrillary tangles, is considered a central mediator of disease pathogenesis. We challenge this classic notion by proposing that tau phosphorylation represents a compensatory response mounted by neurons against oxidative stress and serves a protective function. This novel concept, which can also be applied to protein aggregates in other neurodegenerative diseases, opens a new window of knowledge with broad implications for both the understanding of mechanisms underlying disease pathophysiology and the design of new therapeutic strategies.
Lee
Hyoung-Gon
HG
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106 USA.
Perry
George
G
Moreira
Paula I
PI
Garrett
Matthew R
MR
Liu
Quan
Q
Zhu
Xiongwei
X
Takeda
Atsushi
A
Nunomura
Akihiko
A
Smith
Mark A
MA
D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D006801:Humans; D008870:Microtubules / Q000502:physiology; D016874:Neurofibrillary Tangles / Q000473:pathology; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins