title: Cyclin-dependent kinase 5 activator p25 is generated during memory formation and is reduced at an early stage in Alzheimer's disease.
abstract: BACKGROUND
  The cyclin-dependent kinase 5 activator p35 can be cleaved into p25. Formation of p25 has been suggested to contribute to neurodegeneration in Alzheimer's disease (AD). However, overexpression of low levels of p25 in mice enhances memory formation. Therefore, it has been suggested that p25 formation might be an event early in AD to compensate for impairments in synaptic plasticity. Ongoing p25 formation has been hypothesized to contribute to neurodegeneration at the later stages of AD.
  
  
  METHODS
  Here, we tested the early compensation hypothesis by analyzing the levels of p25 and its precursor p35 in AD postmortem samples from different brain regions at different stages of tau pathology, using quantitative Western blots. Furthermore, we studied p35 and p25 during spatial memory formation. By employing quantitative mass spectrometry, we identified proteins downstream of p25, which were then studied in AD samples.
  
  
  RESULTS
  We found that p25 is generated during spatial memory formation. Furthermore, we demonstrate that overexpression of p25 in the physiological range increases the expression of two proteins implicated in spine formation, septin 7 and optic atrophy 1. We show that the expression of p35 and p25 is reduced as an early event in AD. Moreover, expression of the p25-regulated protein optic atrophy 1 was reduced in a time course similar to p25 expression.
  
  
  CONCLUSIONS
  Our findings suggest that p25 generation is a mechanism underlying hippocampal memory formation that is impaired in the early stages of AD. Our findings argue against the previously raised early compensation hypothesis and they propose that p25-mediated neurotoxicity does not occur in AD.
authors: Department of Neuroscience, Medical Research Council Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK.
authors: Olivia
authors: O
authors: Engmann
authors: Tibor
authors: T
authors: Hortobágyi
authors: Andrew J
authors: AJ
authors: Thompson
authors: Jennifer
authors: J
authors: Guadagno
authors: Claire
authors: C
authors: Troakes
authors: Salvador
authors: S
authors: Soriano
authors: Safa
authors: S
authors: Al-Sarraj
authors: Yong
authors: Y
authors: Kim
authors: Karl Peter
authors: KP
authors: Giese