Abstract

BackgroundIn 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.ResultsUsing 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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0096-z) contains supplementary material, which is available to authorized users.

Highlights

  • Alzheimer’s disease is a devastating neurodegenerative condition and the most prominent cause of dementia

  • CSPalpha expression was reduced before synaptophysin levels drop, suggesting that it contributes to the initial stages of synaptic degeneration

  • Our finding that CSPalpha expression is reduced in AD hippocampus and superior temporal gyrus (STG) is consistent with another study, which was published after we started our project, showing that in Brodmann area 9 of severe Alzheimer’s disease CSPalpha expression is reduced by about 40% [29]

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Summary

Introduction

Alzheimer’s disease is a devastating neurodegenerative condition and the most prominent cause of dementia. Tiwari et al Molecular Brain (2015) 8:6 synaptic chaperone protein cysteine string protein (CSP) alpha [6]. CSPalpha is proposed to serve various functions at the presynapse, including: 1) Formation of a trimeric complex with SGT and Hsc 70, resulting in a CSP/SGT/Hsc chaperone complex that is localised at synaptic vesicles [13] and interacts with SNARE proteins leading to calcium-triggered synaptic vesicle exocytosis [14,15]. The mechanisms underlying synaptic degeneration in Alzheimer’s disease are not well known 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

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