Age‐Dependent Effect of β‐Amyloid Toxicity on Basal Forebrain Cholinergic Neurons and Inflammation in the Rat Brain

Abstract

Beta-amyloid (Aβ) accumulation, neuroinflammation, basal forebrain cholinergic loss and hippocampal degeneration are well-described pathologies associated with Alzheimer's disease (AD). However, the role that age plays in the susceptibility of the brain to these AD pathologies and the relationships between them is still not well understood. This study investigated the age-related response to intracerebroventricular injection of Aβ(25-35) in 3-, 6- and 9-month-old rats. Aβ toxicity resulted in an age-related increase in cholinergic loss and microglial activation in the basal forebrain along with neuronal loss in the hippocampal CA3 subfield. Performance in the Morris water maze revealed impairments in long-term reference memory in 6-month-old Aβ administered animals, which was not seen in 3-month-old animals. These results support a role of Aβ administration in inducing age-dependent cholinergic loss and neuroinflammation, and additionally provide evidence for a more age-appropriate model of adult-onset Aβ toxicity demonstrating pathological changes that reflect the early stages of AD pathogenesis including neuroinflammation, cholinergic loss and beginning stages of memory impairment.

Targeted Antioxidant, Catalase–SKL, Reduces Beta‐Amyloid Toxicity in the Rat Brain

“…Therefore, the aim of the present study was to evaluate whether the targeted antioxidant CAT-SKL is able to reduce the toxicity induced by Ab [25][26][27][28][29][30][31][32][33][34][35] administration in the mature rat brain. Previous work has demonstrated the toxicity induced by intracerebroventricular (icv) administration of Ab [25][26][27][28][29][30][31][32][33][34][35] in the rodent brain, with pathological changes including increased activation of inflammatory cells, loss of hippocampal and cholinergic neurons, and cognitive deficits being realized (2,3,5,22,(40)(41)(42). Results from this study demonstrate the ability of CAT-SKL to reduce Ab induced microglia and astrocyte activation, enhance cholinergic neuronal survival and attenuate long-term reference memory deficits in rats.…”

“…Ab [25][26][27][28][29][30][31][32][33][34][35] or the reverse physiologically inactive, Ab peptide (Bachem, Torrance, CA, USA) was prepared at a concentration of 21.2 lg/lL and administered via icv injection as previously described (22).…”

“…Spatial learning and reference memory were tested in the Morris water maze (MWM) as described previously (22,38). Briefly, animals underwent four days of spatial learning, followed by two probe trials (days 12 and 19) and two days of cued learning (day 20-day 21) ( Figure 1B).…”

“…For histology brain sections were stained with 0.1% Mayer's hematoxylin solution and 0.5% eosin Y solution, dehydrated, and coverslipped. Immunohistochemistry was performed on free-floating serial coronal sections to visualize astrocytes, microglia and cholinergic neurons as previously described (1,2,22). The following primary antibodies were used: mouse monoclonal anti-glial fibrillary acidic protein (GFAP; 1:1000; Sigma-Aldrich, St. Louis MO, USA) to assess astrocyte activation, ramified microglia were detected using a mouse monoclonal antibody OX-6 directed against the MHC II receptor (OX-6; 1:1000; BD Pharmingen, Mississauga ON, Canada) and a monoclonal mouse anticholine acetyltransferase (ChAT; 1:500; Abcam, Cambridge MA, USA) was used to detect cholinergic neurons.…”

Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

“…Intra-cerebroventricular injections of beta-amyloid resulted in age-related increase in cholinergic loss and microglial activation (Nell et al, 2015). Increased neuronal expression of presequence protease (PreP) decreased the accumulation of beta-amyloid in synaptic mitochondria and the neuroinflammatory response (Fang et al, 2015), showing a link between the accumulation of insoluble proteins and neuroinflammation.…”