Alzheimer’s disease (AD) is a progressive neurodegenerative disease that exhibits gradual memory loss. The two histopathological hallmarks of AD are beta-amyloid plaques containing Amyloid beta proteins (Abeta) and neurofibrillary tangles containing phosphorylated tau proteins. Although Abeta and tau proteins have been proposed to be the main contributors to memory loss in AD patients, their roles in different stages of pathological development are still unclear. Recent advances in AD research indicate that brain dysfunction precedes neurodegeneration. Here, we show that early tau-related deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic abnormalities caused by the accumulation of hyperphosphorylated tau within intact dendritic spines, where it disrupts synaptic function by impairing glutamate receptor trafficking or synaptic anchoring. Mutagenesis of 14 disease-associated serine and threonine amino acid residues to create pseudohyperphosphorylated tau caused tau mislocalization while creation of phosphorylation-deficient tau blocked the mis-targeting of tau to dendritic spines. Thus, tau phosphorylation plays a critical role in mediating tau mislocalization and subsequent synaptic impairment. Interestingly, our recent experimental results show that Swedish mutation in Abeta can also aberrantly drive tau proteins to dendritic spines. These data establish that Abeta- and tau-mediated pathologies are likely to converge on dendritic spines.
King's College London (2011) Proc Physiol Soc 22, SA12
Research Symposium: Mediation of synaptic dysfunction by tau mislocalisation to dendritic spines
D. Liao1, B. R. Hoover1,2, M. N. Reed2, J. Su1, R. D. Penrod1, L. A. Kotilinek2, M. K. Grant2, R. Pitstick3, G. A. Carlson3, L. M. Lanier1, L. Yuan1, K. H. Ashe2,1
1. Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States. 2. Neurology, University of Minnesota, Minneapolis, Minnesota, United States. 3. McLaughlin Research Inst, Great Falls, Montana, United States.
View other abstracts by:
Where applicable, experiments conform with Society ethical requirements.