Cholinergic neurodegeneration in an Alzheimer mouse model overexpressing amyloid-precursor protein with the Swedish-Dutch-Iowa mutations

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is mainly characterized by beta-amyloid (Aβ) plaque deposition, Tau pathology and dysfunction of the cholinergic system causing memory impairment. The aim of the present study was to examine (1) anxiety and cognition, (2) Aβ plaque deposition and (3) degeneration of cholinergic neurons in the nucleus basalis of Meynert (nbM) and cortical cholinergic innervation in an Alzheimer mouse model (APP_SweDI; overexpressing amyloid precursor protein (APP) with the Swedish K670N/M671L, Dutch E693Q, and Iowa D694N mutations). Our results show that 12-month-old APP_SweDI mice were more anxious and had more memory impairment. A large number of Aβ plaques were already visible at the age of 6 months and increased with age. A significant decrease in cholinergic neurons was seen in the transgenic mouse model in comparison to the wild-type mice, identified by immunohistochemistry against choline acetyltransferase (ChAT) and p75 neurotrophin receptor as well as by in situ hybridization. Moreover, a significant decrease in cortical cholinergic fiber density was found in the transgenic mice as compared to the wild-type. In the cerebral cortex of APP_SweDI mice, swollen cholinergic varicosities were seen in the vicinity of Aβ plaques. In conclusion, the present study shows that in an AD mouse model (APP_SweDI mice) a high Aβ plaque load in the cortex causes damage to cholinergic axons in the cortex, followed by subsequent retrograde-induced cell death of cholinergic neurons and some forms of compensatory processes. This degeneration was accompanied by enhanced anxiety and impaired cognition.

Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

“…Cognitive impairment along with anxiety in AD animal models, which resembles that in AD patients, has been reported (Foidl et al , 2016; Pietrzak et al , 2015; Sil and Ghosh, 2016; Starkstein et al , 2007). Protofibrillar Aβ 1–42 injection induced anxiety and AD-like pathology in rats (Sharma et al , 2016), suggesting the deleterious effect of elevated Aβ levels on behavior in AD.…”

Neuroprotective efficacy of thymoquinone against amyloid beta-induced neurotoxicity in human induced pluripotent stem cell-derived cholinergic neurons

“…This process of neurodegeneration is triggered by the accumulation of Aβ peptide [5] , which have also been hypothesized to induce neurodegenerative changes at cholinergic terminals [6] . Additionally, other studies revealed that oligomeric Aβ induces cell death [7] , encourages apoptosis by physically piercing the cell membrane, causes neurotoxic cascade and neurodegeneration that leads to AD [8] , [9] .…”

Pharmacological Basis for the Use of Evodiamine in Alzheimer’s Disease: Antioxidation and Antiapoptosis

“…ROS are catalyzed by a combination of redox active metal ions and Aβ in AD [ 4 ]. Severe damage to the cholinergic system, including decreased choline uptake and reduced choline acetyltransferase (ChAT) activity, have been noted in AD patients; meanwhile, the damaged cholinergic system may be further responsible for Aβ plaque formation and increasing phosphorylation of tau protein [ 5 , 6 , 7 ].…”