title: The type of Aβ-related neuronal degeneration differs between amyloid precursor protein (APP23) and amyloid β-peptide (APP48) transgenic mice.
abstract: BACKGROUND
  The deposition of the amyloid β-peptide (Aβ) in the brain is one of the hallmarks of Alzheimer's disease (AD). It is not yet clear whether Aβ always leads to similar changes or whether it induces different features of neurodegeneration in relation to its intra- and/or extracellular localization or to its intracellular trafficking routes. To address this question, we have analyzed two transgenic mouse models: APP48 and APP23 mice. The APP48 mouse expresses Aβ1-42 with a signal sequence in neurons. These animals produce intracellular Aβ independent of amyloid precursor protein (APP) but do not develop extracellular Aβ plaques. The APP23 mouse overexpresses human APP with the Swedish mutation (KM670/671NL) in neurons and produces APP-derived extracellular Aβ plaques and intracellular Aβ aggregates.
  
  
  RESULTS
  Tracing of commissural neurons in layer III of the frontocentral cortex with the DiI tracer revealed no morphological signs of dendritic degeneration in APP48 mice compared to littermate controls. In contrast, the dendritic tree of highly ramified commissural frontocentral neurons was altered in 15-month-old APP23 mice. The density of asymmetric synapses in the frontocentral cortex was reduced in 3- and 15-month-old APP23 but not in 3- and 18-month-old APP48 mice. Frontocentral neurons of 18-month-old APP48 mice showed an increased proportion of altered mitochondria in the soma compared to wild type and APP23 mice. Aβ was often seen in the membrane of neuronal mitochondria in APP48 mice at the ultrastructural level.
  
  
  CONCLUSIONS
  These results indicate that APP-independent intracellular Aβ accumulation in APP48 mice is not associated with dendritic and neuritic degeneration but with mitochondrial alterations whereas APP-derived extra- and intracellular Aβ pathology in APP23 mice is linked to dendrite degeneration and synapse loss independent of obvious mitochondrial alterations. Thus, Aβ aggregates in APP23 and APP48 mice induce neurodegeneration presumably by different mechanisms and APP-related production of Aβ may, thereby, play a role for the degeneration of neurites and synapses.
authors.forename: Ajeet
authors.initials: A
authors.lastname: Rijal Upadhaya
authors.forename: Frederik
authors.initials: F
authors.lastname: Scheibe
authors.forename: Irina
authors.initials: I
authors.lastname: Kosterin
authors.forename: Dorothee
authors.initials: D
authors.lastname: Abramowski
authors.forename: Janina
authors.initials: J
authors.lastname: Gerth
authors.forename: Sathish
authors.initials: S
authors.lastname: Kumar
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.affiliation: Institute of Pathology - Laboratory of Neuropathology, University of Ulm, Ulm, Germany. Dietmar.Thal@uni-ulm.de.
authors.forename: Dietmar Rudolf
authors.initials: DR
authors.lastname: Thal
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology; D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology / Q000502:physiology; D009154:Mutation; D016501:Neurites / Q000473:pathology / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000473:pathology / Q000502:physiology
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)