Levels of soluble and insoluble tau reflect overall status of tau phosphorylation in vivo.
The clinical progression of Alzheimer's disease is closely related to tau pathology. Hyperphosphorylation of tau precedes histopathological evidence of tangle formation, and modulation of tau phosphorylation is a promising therapeutic target. Although some phosphorylation sites are more critical in pathological processes, the importance of each phosphorylation site is unclear. In this study, we found that levels of phosphorylated tau drastically increased in crude and insoluble tau fractions with aging in a transgenic mouse model of Alzheimer-type tauopathy. However, changes in the soluble tau fraction were minor and phosphorylation at some sites was even reduced with aging. Total soluble (presumably functional) tau was reduced, while insoluble tau increased with aging. Synaptic proteins were reduced as insoluble tau increased. Taken together, these findings suggest that levels of soluble and insoluble tau are indicative of overall levels of tau phosphorylation, and may be useful markers to evaluate the effects of anti-tau therapeutic strategies in vivo.
Hirata-Fukae
Chiho
C
Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA.
Li
Hui-Fang
HF
Ma
Li
L
Hoe
Hyang-Sook
HS
Rebeck
G William
GW
Aisen
Paul S
PS
Matsuoka
Yasuji
Y
D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000503:physiopathology; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012995:Solubility; D016708:Synaptophysin / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D016708:Synaptophysin; D016875:tau Proteins; C501447:Dlg4 protein, mouse; C121001:NR2B NMDA receptor; C104722:glutamate receptor ionotropic, AMPA 2