title: Evidence that the presynaptic vesicle protein CSPalpha is a key player in synaptic degeneration and protection in Alzheimer's disease.
abstract: BACKGROUND
  In Alzheimer's disease synapse loss precedes neuronal loss and correlates best with impaired memory formation. However, the mechanisms underlying synaptic degeneration in Alzheimer's disease are not well known. Further, it is unclear why synapses in AD cerebellum are protected from degeneration. Our recent work on the cyclin-dependent kinase 5 activator p25 suggested that expression of the multifunctional presynaptic molecule cysteine string protein alpha (CSPalpha) may be affected in Alzheimer's disease.
  
  
  RESULTS
  Using western blots and immunohistochemistry, we found that CSPalpha expression is reduced in hippocampus and superior temporal gyrus in Alzheimer's disease. Reduced CSPalpha expression occurred before synaptophysin levels drop, suggesting that it contributes to the initial stages of synaptic degeneration. Surprisingly, we also found that CSPalpha expression is upregulated in cerebellum in Alzheimer's disease. This CSPalpha upregulation reached the same level as in young, healthy cerebellum. We tested the idea whether CSPalpha upregulation might be neuroprotective, using htau mice, a model of tauopathy that expresses the entire wild-type human tau gene in the absence of mouse tau. In htau mice CSPalpha expression was found to be elevated at times when neuronal loss did not occur.
  
  
  CONCLUSIONS
  Our findings provide evidence that the presynaptic vesicle protein CSPalpha is a key player in synaptic degeneration and protection in Alzheimer's disease. In the forebrain CSPalpha expression is reduced early in the disease and this may contribute to the initial stages of synaptic degeneration. In the cerebellum CSPalpha expression is upregulated to young, healthy levels and this may protect cerebellar synapses and neurons to survive. Accordingly, CSPalpha upregulation also occurs in a mouse model of tauopathy only at time when neuronal loss does not take place.
authors: Centre for Cellular Basis of Behaviour, Department of Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK. sachin.tiwari@kcl.ac.uk.
authors: Sachin S
authors: SS
authors: Tiwari
authors: Centre for Cellular Basis of Behaviour, Department of Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK. marie.d'orange.11@alumni.ucl.ac.uk.
authors: Marie
authors: M
authors: d'Orange
authors: Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, De Crespigny Park, London, SE5 8AF, UK. claire.troakes@kcl.ac.uk.
authors: Claire
authors: C
authors: Troakes
authors: Centre for Cellular Basis of Behaviour, Department of Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK. badrun.shurovi@kcl.ac.uk.
authors: Badrun N
authors: BN
authors: Shurovi
authors: Centre for Cellular Basis of Behaviour, Department of Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK. olivia.engmann@mssm.edu.
authors: Olivia
authors: O
authors: Engmann
authors: Department of Neuroscience, King's College London, DeCrespigny Park, London, SE5 8AF, UK. wendy.noble@kcl.ac.uk.
authors: Wendy
authors: W
authors: Noble
authors: Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, De Crespigny Park, London, SE5 8AF, UK. tibor.hortobagyi@kcl.ac.uk.|Department of Neuropathology, Institute of Pathology, University of Debrecen, 4032, Debrecen, Hungary. tibor.hortobagyi@kcl.ac.uk.
authors: Tibor
authors: T
authors: Hortobágyi
authors: Centre for Cellular Basis of Behaviour, Department of Neuroscience, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK. Karl.Giese@kcl.ac.uk.|Centre for the Cellular Basis of Behaviour, James Black Centre, King's College London, Institute of Psychiatry, 125 Coldharbour Lane, London, SE5 9NU, UK. Karl.Giese@kcl.ac.uk.
authors: Karl P
authors: KP
authors: Giese
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism / Q000473:pathology; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D000066829:Neuroprotection; D011180:Postmortem Changes; D013569:Synapses / Q000378:metabolism*; D013702:Temporal Lobe; D015854:Up-Regulation; D016875:tau Proteins / Q000378:metabolism
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; C088460:cysteine string protein; D016875:tau Proteins
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