Chronic Progressive Neurodegeneration in a Transgenic Mouse Model of Prion Disease

Abstract

Neurodegenerative diseases present pathologically with progressive structural destruction of neurons and accumulation of mis-folded proteins specific for each condition leading to brain atrophy and functional disability. Many animal models exert deposition of pathogenic proteins without an accompanying neurodegeneration pattern. The lack of a comprehensive model hinders efforts to develop treatment. We performed longitudinal quantification of cellular, neuronal and synaptic density, as well as of neurogenesis in brains of mice mimicking for genetic Creutzfeldt-Jacob disease as compared to age-matched wild-type mice. Mice exhibited a neurodegenerative process of progressive reduction in cortical neurons and synapses starting at age of 4–6 months, in accord with neurologic disability. This was accompanied by significant decrease in subventricular/subependymal zone neurogenesis. Although increased hippocampal neurogenesis was detected in mice, a neurodegenerative process of CA1 and CA3 regions associated with impaired hippocampal-dependent memory function was observed. In conclusion, mice exhibit pathological neurodegeneration concomitant with neurological disease progression, indicating these mice can serve as a model for neurodegenerative diseases.

Dysregulation of neuroprotective astrocytes, a spectrum of microglial activation states, and altered hippocampal neurogenesis are revealed by single-cell RNA sequencing in prion disease

“…8 B). This was consistent with a number of studies that have detected increased neurogenesis in the hippocampus [ 20 , 22 ] which may protect against prion disease [ 34 ]. Relatively few transcripts of neural progenitors were differentially expressed (Fig.…”

“…Interestingly, we observed increased relative frequency of proliferating cell populations in the prion-infected brain, including neural progenitor cells, oligodendrocyte progenitor cells and proliferating microglial subtypes. While the relative frequencies presented here do not equate to true measurements of absolute cell count, previous studies have implicated proliferation of microglia [ 74 ] and neural progenitor cells [ 20 , 22 ] during prion disease. We speculate that a common means exists to promote cell proliferation during prion disease—possibly in an unsuccessful attempt to restore brain cells that are lost during disease.…”

Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability

“…For example, different studies reported reduced [40][41][42][43], normal [25], or enhanced [19,44] long-term potentiation (LTP) in Prnp 0/0 mice compared to wild-type mice. Following these descriptions, the consequences of Prnp absence in memory, learning, and behavior lead to variable results in studies using mice carrying FGs [24,[45][46][47][48] or not [42,49].…”

Behavioral deficits, learning impairment, and enhanced hippocampal excitability in co-isogenic PrnpZH3/ZH3 mice

“…For example, different studies reported reduced (Collinge et al, 1994;Criado et al, 2005;Curtis et al, 2003;Manson et al, 1995), normal (Lledo et al, 1996), or enhanced (Maglio et al, 2006;Rangel et al, 2009) long-term potentiation (LTP) in Prnp 0/0 mice compared to wild-type mice. Following these descriptions, the consequences of Prnp absence in memory, learning, and behavior include variable results in studies using mice carrying FGs (i.e., (Bueler et al, 1992;Coitinho et al, 2003;Fainstein et al, 2016;Lipp et al, 1998;Schmitz et al, 2014b)) or not (i.e., (Criado et al, 2005;Manson et al, 1994)).…”

“…For example, different studies reported reduced [40][41][42][43], normal [25], or enhanced [19,44] long-term potentiation (LTP) in Prnp 0/0 mice compared to wild-type mice. Following these descriptions, the consequences of Prnp absence in memory, learning, and behavior lead to variable results in studies using mice carrying FGs [24,[45][46][47][48] or not [42,49].…”