Cholinergic neurodegeneration in an Alzheimer mouse model overexpressing amyloid-precursor protein with the Swedish-Dutch-Iowa mutations.
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.
Laboratory of Psychiatry and Exp. Alzheimer's Research, Department of Psychiatry and Psychotherapy, Medical University of Innsbruck, Austria.
Bettina Maria
BM
Foidl
Laboratory of Psychiatry and Exp. Alzheimer's Research, Department of Psychiatry and Psychotherapy, Medical University of Innsbruck, Austria.
Patricia
P
Do-Dinh
Laboratory of Psychiatry and Exp. Alzheimer's Research, Department of Psychiatry and Psychotherapy, Medical University of Innsbruck, Austria.
Bianca
B
Hutter-Schmid
Laboratory of Psychiatry and Exp. Alzheimer's Research, Department of Psychiatry and Psychotherapy, Medical University of Innsbruck, Austria; Department of Psychology, University of Innsbruck, Austria.
Harald R
HR
Bliem
Laboratory of Psychiatry and Exp. Alzheimer's Research, Department of Psychiatry and Psychotherapy, Medical University of Innsbruck, Austria. Electronic address: christian.humpel@i-med.ac.at.
Christian
C
Humpel
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D020532:Basal Nucleus of Meynert / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D059329:Cholinergic Neurons / Q000473:pathology*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor
Alzheimer; Cholinergic neurodegeneration; Plaques; Transgenic mice
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