Abstract
BackgroundThe 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.ResultsTracing 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-1-77) contains supplementary material, which is available to authorized users.
Highlights
The deposition of the amyloid β-peptide (Aβ) in the brain is one of the hallmarks of Alzheimer’s disease (AD)
As previously published 15-month-old APP23 mice exhibited a high number of extracellular Aβ-plaques in the cerebral cortex (Figure 2a - indicated by arrows) as well as cerebral amyloid angiopathy as previously described in male and female animals [37]
This study shows that amyloid precursor protein (APP)-derived extra-and intracellular Aβ pathology in 15-month-old APP23 mice was associated with neuron loss, synapse loss and with neuritic alterations in non-apoptotic and non-necrotic neurons
Summary
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. 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 is an Aβ-plaque producing mouse model, which overexpresses human APP with the Swedish mutation (KM670/671NL) in CNS neurons It exhibits dendrite degeneration, loss of CA1 neurons and of asymmetric synapses in the frontocentral cortex [17,18,19]. We investigated 1) any pathological abnormalities associated with APP-independent intracellular Aβ accumulation in APP48 mice and 2) whether APP and Aβ production by β- and γ-secretase is critical for neurodegeneration in APP23 mice rather than the mere presence of the Aβ peptide as in APP48 mice
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