Early improved and late defective cognition is reflected by dendritic spines in Tau.P301L mice

Abstract

Cognitive demise correlates with progressive brain tauopathy in dementing patients. Improved cognition of young Tau.P301L mice contrasts with dysfunction later in life and remains unexplained (Boekhoorn et al., 2006). To unravel early mechanisms, we composed a correlative time line of clinical symptoms, cognitive defects, and biochemical and pathological traits, including comprehensive analysis of dendritic spines in specified region soft hecortex and hippocampus of young and adult Tau.P301Lmice.Remarkably,youngTau.P301L mice have not more, but more mature spines than wild-type mice, revealing the anatomical substrate for their improved cognition and LTP. Spine maturation remained high in the hippocampus of adult Tau.P301L mice. However, spines regressed in length paralleling impaired cognition and increased Tau phosphorylation (Terweletal., 2005). Conversely, spine maturation was unaffected in adult Tau.4R mice, while spine density was increased and length reduced similar to Tau.P301L mice. To explain how protein Tau promoted spinogen-esis, we analyzed hippocampal synaptosomes and dendritic spinesfor mouse andhuman Tau. While synaptosomes were positive for both mouse and human Tau, weak variable reaction in spines was observedonly after fixation according to Bouin. Mouse Tau was absent from spinesinwild-type mice, dissociating the pathological actions of Tau intransgenic miceby relocalization into dendrites and spines from the physiological actions of protein Tau in axons only. We conclude that mutant protein Tau modulates cognition and morphology of spines similarly and in both directions, with pathology later in life coinciding with increased phosphorylation and relocalization of Tau from axons to soma and processes. © 2011 the authors.