Evidence that the presynaptic vesicle protein CSPalpha is a key player in synaptic degeneration and protection in Alzheimer's disease

Sachin S. Tiwari, Marie d'Orange, Claire Troakes, Badrun N. Shurovi, Olivia Engmann, Wendy Noble, T. Hortobágyi, Karl P. Giese

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

CONCLUSION: 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.

Original languageEnglish
Number of pages1
JournalMolecular Brain
Volume8
DOIs
Publication statusPublished - Jan 29 2015

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Alzheimer Disease
Proteins
Cerebellum
Tauopathies
Synapses
Up-Regulation
cysteine string protein
Cyclin-Dependent Kinase 5
Synaptophysin
Temporal Lobe
Prosencephalon
Hippocampus
Western Blotting
Immunohistochemistry
Neurons
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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Evidence that the presynaptic vesicle protein CSPalpha is a key player in synaptic degeneration and protection in Alzheimer's disease. / Tiwari, Sachin S.; d'Orange, Marie; Troakes, Claire; Shurovi, Badrun N.; Engmann, Olivia; Noble, Wendy; Hortobágyi, T.; Giese, Karl P.

In: Molecular Brain, Vol. 8, 29.01.2015.

Research output: Contribution to journalArticle

Tiwari, Sachin S. ; d'Orange, Marie ; Troakes, Claire ; Shurovi, Badrun N. ; Engmann, Olivia ; Noble, Wendy ; Hortobágyi, T. ; Giese, Karl P. / Evidence that the presynaptic vesicle protein CSPalpha is a key player in synaptic degeneration and protection in Alzheimer's disease. In: Molecular Brain. 2015 ; Vol. 8.
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AU - Noble, Wendy

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