Loss of Cerebellar Granule Neurons Is Associated With Punctate but Not With Large Focal Deposits of Prion Protein in Creutzfeldt-Jakob Disease

Baptiste A. Faucheux, Nicolas Privat, Jean-Philippe Brandel, Véronique Sazdovitch, Jean-Louis Laplanche, Claude-Alain Maurage, Jean-Jacques Hauw, Stéphane Haïk
2009 Journal of Neuropathology and Experimental Neurology  
Whether aggregates of prion protein (PrP) reflect neurotoxicity or are neuroprotective in prion diseases is unclear. To address this question, we performed a clinicopathologic study of cerebellar granular neurons in 100 patients affected with sporadic Creutzfeldt-Jakob disease (CJD). There was significant loss of these neurons in the subset of cases with Val/Val genotype at PRNP Codon 129 and Molecular Isotype 2 of abnormal PrP (sporadic CJD-VV2) (n = 32) compared with both the other CJD
more » ... s and to controls. Pathological PrP deposits of the punctate-type (synaptic-type) in this subgroup correlated with neuronal loss and proliferation of astrocytes and microglia. By contrast, the numbers of large deposits (5-to 50-Km-diameter) and numbers of amyloid plaques did not correlate with neuronal loss. These findings are consistent with the view that large aggregates may protect neurons by sequestering neurotoxic PrP oligomers, whereas punctate deposits may indicate the location of neuronal death processes in CJD. FIGURE 3. Cerebellar granule neuron degeneration in Val/Val genotype at PRNP Codon 129 and Molecular Isotype 2 of abnormal prior protein ([PrP] sporadic Creutzfeldt-Jakob disease-VV2) patients correlates with glial activation and associated with diffuse punctate PrP deposits. The relationships between mean numerical density of cells and quantitation of punctate PrP deposits (synaptic-type) (SD) are shown. Mean cell counts for neurons, astrocytes, and microglial cells were determined for each score of punctate PrP Sc deposits in the cerebellar granular layer (gL) and molecular layer (mL); values are plotted with respect to punctate PrP deposition scores. Marked loss of cerebellar granule neurons and increased glial cell densities are associated with punctate deposits detected in the gL and in the mL at some distance from the cell bodies of the cerebellar granule neurons. Cerebellar granule neurons ( & ), astrocytes (h, AgL; g, AmL), microglial cells (r, MgL; $, MmL), and punctate PrP deposition in the gL (A) and mL (B).
doi:10.1097/nen.0b013e3181af7f23 pmid:19606064 fatcat:5kduhw2fgrbj5gfemxm6o5cje4