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The type of A?-related neuronal degeneration differs between amyloid precursor protein (APP23) and amyloid ?-peptide (APP48) transgenic mice.
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ABSTRACT: Background
The deposition of the amyloid ?-peptide (A?) in the brain is one of the hallmarks of Alzheimer's disease (AD). It is not yet clear whether A? 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 A?1-42 with a signal sequence in neurons. These animals produce intracellular A? independent of amyloid precursor protein (APP) but do not develop extracellular A? plaques. The APP23 mouse overexpresses human APP with the Swedish mutation (KM670/671NL) in neurons and produces APP-derived extracellular A? plaques and intracellular A? 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. A? was often seen in the membrane of neuronal mitochondria in APP48 mice at the ultrastructural level.Conclusions
These results indicate that APP-independent intracellular A? accumulation in APP48 mice is not associated with dendritic and neuritic degeneration but with mitochondrial alterations whereas APP-derived extra- and intracellular A? pathology in APP23 mice is linked to dendrite degeneration and synapse loss independent of obvious mitochondrial alterations. Thus, A? aggregates in APP23 and APP48 mice induce neurodegeneration presumably by different mechanisms and APP-related production of A? may, thereby, play a role for the degeneration of neurites and synapses.
SUBMITTER: Rijal Upadhaya A
PROVIDER: S-EPMC4046770 | biostudies-literature | 2013 Nov
REPOSITORIES: biostudies-literature
Publications
The type of Aβ-related neuronal degeneration differs between amyloid precursor protein (APP23) and amyloid β-peptide (APP48) transgenic mice.
Acta neuropathologica communications 20131118
<h4>Background</h4>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 ...[more]