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Selective presynaptic degeneration in the synaptopathy associated with ME7-induced hippocampal pathology

Bryony C Gray1, Zuzana Siskova, V Hugh Perry

  • 1School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton, Hants, UK.

Neurobiology of Disease
|April 14, 2009
PubMed

Insights

Prion disease models show early loss of presynaptic proteins and synapses in the hippocampus. This "synaptopathy" may be the first sign of neuronal dysfunction in neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Prion Disease Research
  • Neurodegeneration

Background:

  • Prion diseases are characterized by misfolded prion protein (PrPSc) accumulation.
  • The ME7 strain in mice provides a model for studying prion disease progression.
  • Early neuronal dysfunction in prion diseases remains incompletely understood.

Purpose of the Study:

  • To investigate early synaptic changes in a mouse model of prion disease.
  • To determine the relationship between PrPSc accumulation and presynaptic alterations.
  • To identify potential earliest markers of neuronal dysfunction.

Main Methods:

  • Intrahippocampal injection of ME7 prion homogenate in mice.
  • Biochemical analysis of presynaptic protein expression at 8, 12, and 21 weeks.
  • Electron microscopy to assess synaptic morphology and density.
  • Evaluation of postsynaptic changes in relation to presynaptic integrity.

Main Results:

  • Misfolded prion protein (PrPSc) accumulation correlated with reduced presynaptic protein expression.
  • Synapse numbers progressively decreased in the stratum radiatum.
  • An increase in postsynaptic specializations without intact presynaptic partners was observed.
  • Presynaptic compartment disruption occurred independently of CA3 neuron cell body loss.

Conclusions:

  • Selective presynaptic pathology, termed "synaptopathy," occurs early in ME7 prion disease.
  • This synaptopathy may represent the initial neuronal dysfunction in prion and other protein misfolding neurodegenerative diseases.
  • Early synaptic disruption precedes significant cell body loss, highlighting its role in disease pathogenesis.

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