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Endogenous murine A? increases amyloid deposition in APP23 but not in APPPS1 transgenic mice.

ABSTRACT: Endogenous murine amyloid-? peptide (A?) is expressed in most A? precursor protein (APP) transgenic mouse models of Alzheimer's disease but its contribution to ?-amyloidosis remains unclear. We demonstrate ? 35% increased cerebral A? load in APP23 transgenic mice compared with age-matched APP23 mice on an App-null background. No such difference was found for the much faster A?-depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice codeposited murine A?, and immunoelectron microscopy revealed a tight association of murine A? with human A? fibrils. Deposition of murine A? was considerably less efficient compared with the deposition of human A? indicating a lower amyloidogenic potential of murine A? in vivo. The amyloid dyes Pittsburgh Compound-B and pentamer formyl thiophene acetic acid did not differentiate between amyloid deposits consisting of human A? and deposits of mixed human-murine A?. Our data demonstrate a differential effect of murine A? on human A? deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse A? may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies.

SUBMITTER: Mahler J

PROVIDER: S-EPMC4457564 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Project description: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.

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Endogenous murine A? increases amyloid deposition in APP23 but not in APPPS1 transgenic mice.

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