Long-term effects of selective immunolesions of cholinergic neurons of the nucleus basalis magnocellularis on the ascending cholinergic pathways in the rat: A model for Alzheimer's disease

Abstract

Alzheimer's disease is associated with a significant decrease in the cholinergic input to the neocortex. In a rat model of this depletion, we analyzed the subsequent long-term changes in cholinergic fiber density in two well-defined areas of the frontal and parietal cortices: Fr1, the primary motor cortex, and HL, the hindlimb area of the somatosensory (parietal) cortex, two cortical cholinergic fields that receive inputs from the nucleus basalis magnocellularis (nBM). A specific cholinergic lesion was induced by the intraparenchymal injection of 192 IgG-saporin into the nBM. Choline acetyltransferase (ChAT) immunohistochemistry was applied to identify the loss of cholinergic neurons in the nBM, while acetylcholinesterase (AChE) enzyme histochemistry was used to analyze the decreases in the number of cholinoceptive neurons in the nBM and the cholinergic fiber density in the Fr1 and HL cortical areas in response to the nBM lesion. The immunotoxin differentially affected the number of ChAT- and AChE-positive neurons in the nBM. 192 IgG-saporin induced a massive, irreversible depletion of the ChAT-positive (cholinergic) neurons (to 11.7% of the control level), accompanied by a less dramatic, but similarly persistent loss of the AChE-positive (cholinoceptive) neurons (to 59.2% of the control value) in the nBM within 2 weeks after the lesion. The difference seen in the depletion of ChAT- and AChE-positive neurons is due to the specificity of the immunotoxin to cholinergic neurons. The cholinergic fiber densities in cortical areas Fr1 and HL remained similarly decreased (to 62% and 68% of the control values, respectively) up to 20 weeks. No significant rebound in AChE activity occurred either in the nBM or in the cortices during the period investigated. This study therefore demonstrated that, similarly to the very extensive reduction in the number of ChAT-positive neurons in the nBM, cortical areas Fr1 and HL underwent long-lasting reductions in the number of AChE-positive fibers in response to specific cholinergic lesioning of the nBM.

AUTEN-67 (Autophagy Enhancer-67) Hampers the Progression of Neurodegenerative Symptoms in a Drosophila model of Huntington’s Disease

“…For identification of neurons and demonstration of the presence of ubiquitinated proteins in the autophagy pathway, anti-NeuN and anti-p62 antibodies were used in consecutive sections. NeuN and SQSTM1/p62 immunohistochemistry was performed as described [30]. For antigen recovery, deparaffinized sections were boiled in 0.01 M citrate-buffer solution (pH 6.0) in a microwave oven for 2 min (set at 900 watts).…”

Neurotrophic factors rescue basal forebrain cholinergic neurons and improve performance on a spatial learning test

“…Treatment with the 192 IgG saporin leads to the loss of a large portion of the BFCNs (Ha et al, 1999; Johnson et al, 2002; Pappas and Sherren, 2003; Ricceri et al, 2004; Robertson et al, 1998; Szigeti et al, 2013). Although it is known that saporin is able to kill cells by inactivating ribosomes and thereby shutting down protein synthesis (Daniels-Wells et al, 2013), it is not yet clear how a partial, sublethal (to the cell) dose may affect the cell.…”

“…Experimental damage to BFCNs in laboratory animals has been shown to lead to deficits in learning and memory tasks, particularly those related to spatial memory (Johnson et al, 2002; Ricceri et al, 2004; Marques Pereira et al, 2005; Deiana et al, 2011). In addition, specific cholinergic lesions of the nBM can lead to the long-lasting reduction of acetylcholinesterase (AChE) positive fibers in the cerebral cortex (Szigeti et al 2013). These results from laboratory animals have supported the idea that loss of cholinergic function in humans is associated with diminished cognitive abilities and may contribute to the development of Alzheimer’s disease (Bartus et al, 1982; Perry et al, 1992; Mufson et al, 1999; Auld et al, 2002; Tuszynski et al, 2005; Craig et al, 2011).…”

Streptavidin-Saporin: Converting Biotinylated Materials into Targeted Toxins

“…As such, a toxin that removed these cells from the rat basal forebrain provided an excellent model for some of the facets of AD. It is a validated model for the disease [ 17 , 18 , 19 , 20 , 21 , 22 ]. The use of an antibody to a cell-surface brain marker for lesioning was firmly established in a series of papers [ 23 , 24 , 25 , 26 ].…”