Abstract
Alzheimer’s disease (AD) is associated with degeneration of cholinergic neurons in the basal forebrain. Administration of the immunotoxin 192IgG-saporin to rats, an animal model of AD, leads to degeneration of cholinergic neurons in the medial septal area. In the present study, cholinergic cell death was induced by intracerebroventricular administration of 192IgG-saporin. One and a half months after injection, we studied the histopathology of the hippocampus and the responses of microglia and astrocytes using immunohistochemistry and neuroglial gene expression. We found that treatment with 192IgG-saporin resulted in neuronal loss in the CA3 field of the hippocampus. Microglial proliferation was observed in the dentate gyrus of the dorsal hippocampus and white matter. Massive proliferation and activation of microglia in the white matter was associated with strong activation of astrocytes. However, the expression of microglial marker genes significantly increased only in the dorsal hippocampus, not the ventral hippocampus. These effects were not related to non-specific action of 192IgG-saporin because of the absence of the Nerve growth factor receptor in the hippocampus. Additionally, 192IgG-saporin treatment also induced a decrease in the expression of genes that are associated with transport functions of brain vascular cells (Slc22a8, Ptprb, Sdpr), again in the dorsal hippocampus but not in the ventral hippocampus. Taken together, our data suggest that cholinergic degeneration in the medial septal area induced by intracerebroventricular administration of 192IgG-saporin results in an increase in the number of microglial cells and neuron degeneration in the dorsal hippocampus.
Highlights
Impairment of cholinergic neurotransmission is a characteristic feature of different neurodegenerative diseases including Alzheimer’s disease (AD) (Hampel et al, 2018), Parkinson’s disease with dementia, and dementia with Lewy bodies (DLB) (Liu et al, 2018)
Microglial cells in all areas studied [dentate gyrus (DG), CA1 and CA3 areas] had small bodies and thin ramified processes (Figure 1), i.e., microglial morphology that is typical of resting cells
In addition to the hippocampus, we analyzed the state of microglia in the white matter localized between the neocortex and hippocampus (Figures 1G,H)
Summary
Impairment of cholinergic neurotransmission is a characteristic feature of different neurodegenerative diseases including Alzheimer’s disease (AD) (Hampel et al, 2018), Parkinson’s disease with dementia, and dementia with Lewy bodies (DLB) (Liu et al, 2018). Parkinson’s disease with dementia is associated with a decrease in the number of cholinergic neurons in the NBM but not in the medial septum and DBB area (Hall et al, 2014). The DLB is associated with a loss of cholinergic neurons in both the NBM and the medial septum and DBB area (Fujishiro et al, 2006). One widely used approach for the analysis of the consequences of cholinergic degeneration in the brain is induction of selective death of cholinergic neurons by the immunotoxin 192IgG-saporin (Ig-saporin), which is injected either intracerebroventricularly or intraseptally (Wiley et al, 1991; Heckers et al, 1994; Schliebs et al, 1996; Potter et al, 1999). Ig-saporin selectively eliminates cholinergic neurons in the septum and DBB area after either intraseptal or intracerebroventricular injection and does not affect other neuronal populations in these regions (Heckers et al, 1994; Johnson et al, 2002)
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