Early unsuspected neuron and axon terminal loss in scra pie‐infected mice revealed by morphometry and immunocytochemistry

Abstract

Neuronal loss is often quoted as an element of the pathology of the transmissible spongiform encephalopathies, but few data are published. To determine whether neuronal loss is a salient feature of murine scrapie, and whether there is a relationship with the other hallmark lesions of scrapie we compared the numbers of neurons, severity of vacuolation, axonal bouton density and distribution of prion protein (PrP) in the dorsal lateral geniculate nucleus (dLGN) following intraocular infection of C57BL/FaBtDk mice with ME7 scrapie. This route of infection limits the initial spread of infection to the retinal efferents, thus directing infectivity and subsequent pathological changes to the dLGN which is a major projection of the optic nerve. Morphometric assessment of neuron number in the dLGN was made on semi-serial sections from five infected and five normal brain injected controls at four 50-day intervals during the incubation period, and on terminally affected mice. The number of neurons decreased from around 20,000 at 50 days to under 1000 in the terminal group. Significant loss was identified in individual mice at 150 days post-infection, coincident with the onset of vacuolation: neuron number was found to have an inverse relationship to the severity of vacuolation. Axonal boutons in the dLGN (demonstrated by synaptophysin immunolabelling) were reduced at 200 days, and virtually absent in terminal mice. The intensity of PrP immunostaining progressively increased from 150 days, and in a separate experiment PrP was detected from 175 days by polyacrylamide gel electrophoresis of brain extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Degenerating Synaptic Boutons in Prion Disease

“…26,27,28 Electron microscopy revealed the well-described ultrastructural hallmarks of the pathology in prion diseased brain 29 and these were present in all ME7-animals from 12 weeks p.i. onwards.…”

“…The dendritic alterations and loss of hippocampal pyramidal neurons have been documented in prion strains additional to ME7 32 and by different routes of challenge than intracerebral. 26 These Synaptic Degeneration in Prion Disease 1613 AJP October 2009, Vol. 175, No.…”

Upregulation of the Genes Encoding Lysosomal Hydrolases, a Perforin-Like Protein, and Peroxidases in the Brains of Mice Affected with an Experimental Prion Disease

“…Several reports have indicated the involvement of an apoptotic process in neuronal cell death (13,15,34). For instance, Giese et al (13) demonstrated apoptosis of neurons in the brain of a mouse with experimental prion disease by using the in situ end-labeling technique.…”

Altered Interaction and Expression of Proteins Involved in Neurosecretion in Scrapie-infected GT1-1 Cells

“…These observations confirm previous studies of synaptic protein expression due to prion infection in vivo. Prion diseases are associated with synaptic disorganization and reduction as seen in brains from both patients with CJD (3, 4) and scrapieinfected mice (7,(53)(54)(55)(56). The degeneration and loss of axon terminals occur early during scrapie infections, and in mice it precedes a dendritic spine loss and neuronal cell death (53,55,56).…”

“…The vacuoles that give the spongiform character of the degeneration are mainly located in dendrites, which also show varicosities and loss of spines as revealed in Golgi-impregnated specimen (2). In addition to these dendritic changes, reduced expression of presynaptic marker proteins, such as synaptophysin, synaptic-associated protein of molecular weight 25,000 (SNAP-25), 1 syntaxin 1, synapsin 1, and ␣-and ␤-synuclein, has been reported in both clinical materials (3-6) and animal experimental models (7,8) indicating that presynaptic axon terminals are also affected. The mechanisms behind the presynaptic changes and their potential pathogenetic role in the disease are not known.…”