Abstract
Amyloid precursor protein (APP) transgenic animal models of Alzheimer’s disease have become versatile tools for basic and translational research. However, there is great heterogeneity of histological, biochemical, and functional data between transgenic mouse lines, which might be due to different transgene expression patterns. Here, the expression of human APP (hAPP) by GABAergic hippocampal interneurons immunoreactive for the calcium binding proteins parvalbumin, calbindin, calretinin, and for the peptide hormone somatostatin was analyzed in Tg2576 mice by double immunofluorescent microscopy. Overall, there was no GABAergic interneuron subpopulation that did not express the transgene. On the other hand, in no case all neurons of such a subpopulation expressed hAPP. In dentate gyrus molecular layer and in stratum lacunosum moleculare less than 10% of hAPP-positive interneurons co-express any of these interneuron markers, whereas in stratum oriens hAPP-expressing neurons frequently co-express these interneuron markers to different proportions. We conclude that these neurons differentially contribute to deficits in young Tg2576 mice before the onset of Abeta plaque pathology. The detailed analysis of distinct brain region and neuron type-specific APP transgene expression patterns is indispensable to understand particular pathological features and mouse line-specific differences in neuronal and systemic functions.
Highlights
Alzheimer’s disease (AD) is histopathologically characterized by the formation of intracellular neurofibrillary tangles, principally made of tau protein and extracellular amyloid deposits composed of Abeta peptides that deposit in the parenchyma and in the vessel walls
A substantial gain of knowledge on mechanisms of amyloid pathology in AD was achieved by the analyses of transgenic mouse models overexpressing human Amyloid precursor protein (APP) with diseasepromoting mutations that lead to early-onset AD in humans (Ameen-Ali et al, 2017; Sasaguri et al, 2017)
HAPP-specific rat monoclonal antibody we have recently demonstrated transgene expression by virtually all CA1 to CA3 pyramidal neurons and by scattered GABAergic interneurons throughout all hippocampal layers, but not by dentate gyrus (DG) granule cells (Höfling et al, 2016)
Summary
Alzheimer’s disease (AD) is histopathologically characterized by the formation of intracellular neurofibrillary tangles, principally made of tau protein and extracellular amyloid deposits composed of Abeta peptides that deposit in the parenchyma and in the vessel walls. A substantial gain of knowledge on mechanisms of amyloid pathology in AD was achieved by the analyses of transgenic mouse models overexpressing human APP (hAPP) with diseasepromoting mutations that lead to early-onset AD in humans (Ameen-Ali et al, 2017; Sasaguri et al, 2017). These animal models differ significantly regarding the onset of pathology, spatial appearance of Abeta deposits, neuronal loss and deficits in learning and memory tasks as reviewed by Höfling et al (2016) which hampers drawing general conclusions on defined pathogenic functions of Abeta peptides. These mice overexpress hAPP harboring the Swedish double mutation KM670/671NL and develop Abeta deposits starting in entorhinal cortex followed by hippocampus at around 11 months of age (Hsiao et al, 1996; Kawarabayashi et al, 2001; Hartlage-Rübsamen et al, 2011)
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