Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein-specific antibodies (original) (raw)
Expression of endogenous mouse APP modulates β-amyloid deposition in hAPP-transgenic mice
Acta neuropathologica communications, 2017
Amyloid-β (Aβ) deposition is one of the hallmarks of the amyloid hypothesis in Alzheimer's disease (AD). Mouse models using APP-transgene overexpression to generate amyloid plaques have shown to model only certain parts of the disease. The extent to which the data from mice can be transferred to man remains controversial. Several studies have shown convincing treatment results in reducing Aβ and enhancing cognition in mice but failed totally in human. One model-dependent factor has so far been almost completely neglected: the endogenous expression of mouse APP and its effects on the transgenic models and the readout for therapeutic approaches.Here, we report that hAPP-transgenic models of amyloidosis devoid of endogenous mouse APP expression (mAPP-knockout / mAPPko) show increased amounts and higher speed of Aβ deposition than controls with mAPP. The number of senile plaques and the level of aggregated hAβ were elevated in mAPPko mice, while the deposition in cortical blood vess...
Endogenous murine Aβ increases amyloid deposition in APP23 but not in APPPS1 transgenic mice
Neurobiology of Aging, 2015
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The Journal of Comparative Neurology, 1994
The P-amyloid or A4 protein is found deposited in neuritic plaques and neurofibrillary tangles in Alzheimer's disease (AD) affected brains and in the brains of adults with Down's Syndrome. The precursor to this 42 amino acid protein is the 695 amino acid long amyloid protein precursor (APP-695). Two additional APP species, APP-751 and APP-770, each contain a 56-amino-acid insert sequence that is analogous to Kunitz protease inhibitors. APP mRNA is widely distributed in both the human and rat brain, although the adult rat does not develop mature amyloid pathology. In this study we used antibodies against the N-terminus, junction site (unique to APP-695) insert sequence (unique to APP-751,-770), A4 region, and C-terminus of APP to immunolabel sections from throughout the young adult rat brain. From these results we constructed maps of the staining pattern of each antibody. We found that APP is widely distributed throughout the brain, that labelling is predominantly neuronal in character, and that there is marked variation among the antibodies in the extent of labelling, the particular cell populations stained, and the structures labelled within individual cells. The differential staining patterns observed with the five different antibodies suggest that the way APP is processed differs from one region to another and within different compartments in the cell. The specificity of the antibodies was established by Western blot analysis, in which APP species of approximately 95 and 110 kD were found. Our findings on the distribution of APP provide a foundation for further investigations into the normal role of APP and the pathogenesis of AD.
A transgenic rat expressing human APP with the Swedish Alzheimer’s disease mutation
Biochemical and Biophysical Research Communications, 2007
In recent years, transgenic mice have become valuable tools for studying mechanisms of Alzheimer's disease (AD). With the aim of developing an animal model better for memory and neurobehavioural testing, we have generated a transgenic rat model of AD. These animals express human amyloid precursor protein (APP) containing the Swedish AD mutation. The highest level of expression in the brain is found in the cortex, hippocampus, and cerebellum. Starting after the age of 15 months, the rats show increased tau phosphorylation and extracellular Ab staining. The Ab is found predominantly in cerebrovascular blood vessels with very rare diffuse plaques. We believe that crossing these animals with mutant PS1 transgenic rats will result in accelerated plaque formation similar to that seen in transgenic mice.
Proceedings of the National Academy of Sciences, 2009
The hypothesis that amyloid-β (Aβ) peptides are the primary cause of Alzheimer's disease (AD) remains the best supported theory of AD pathogenesis. Yet, many observations are inconsistent with the hypothesis. Aβ peptides are generated when amyloid precursor protein (APP) is cleaved by presenilins, a process that also produces APP intracellular domain (AICD). We previously generated AICD-overexpressing transgenic mice that showed abnormal activation of GSK-3β, a pathological feature of AD. We now report that these mice exhibit additional AD-like characteristics, including hyperphosphorylation and aggregation of tau, neurodegeneration and working memory deficits that are prevented by treatment with lithium, a GSK-3β inhibitor. Consistent with its potential role in AD pathogenesis, we find AICD levels to be elevated in brains from AD patients. The in vivo findings that AICD can contribute to AD pathology independently of Aβ have important therapeutic implications and may explain so...
Frontiers in Neuroscience
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 coexpress 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.
The FASEB Journal, 2005
Alzheimer's disease is characterized by brain deposition of toxic amyloid beta-peptide (Abeta), generated from the Abeta precursor protein (APP). APP gene expression is regulated via the proximal promoter region (PPR; -46/-1 in the human sequence; +1 transcription start) and the 5'-untranslated region (5'-UTR; +1/+147). We have recently identified a unique CAGA sequence, "amyloid" (+83/+86) present only in the APP gene from amyloid plaque-forming species, absent in all APP-like-proteins' (APLP1 and APLP2) genes. To assay functional activity of PPR + UTR and 5'-UTR regions that either contain or lack the "amyloid" box, we tested nine constructs in transient transfection studies. We observed significantly high reporter gene activity with -46/144, -46/100, -46/54, and 54/144 constructs. The 54/100 fragment, which contains a transforming growth factor-beta/ "amyloid"/interleukin-1 acute box cassette, showed different activity depending o...