[ { "id": "authors:gf9ht-9mh65", "collection": "authors", "collection_id": "gf9ht-9mh65", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150504-134643774", "type": "conference_item", "title": "Witnessing microtubule-based transport in the living brain: Impact of the cargomotor receptor, amyloid precursor protein, and Alzheimer's plaques", "author": [ { "family_name": "Chaves", "given_name": "F. L.", "clpid": "Chaves-F-L" }, { "family_name": "Medina", "given_name": "C. S.", "clpid": "Medina-C-S" }, { "family_name": "Zhang", "given_name": "X.", "clpid": "Zhang-X" }, { "family_name": "Jacobs", "given_name": "R. E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" }, { "family_name": "Bearer", "given_name": "E. L.", "clpid": "Bearer-E-L" } ], "contributor": [ { "family_name": "Lippincott-Schwartz", "given_name": "Jennifer", "clpid": "Lippincott-Schwartz-J" }, { "family_name": "Marshall", "given_name": "Wallace", "clpid": "Marshall-W" }, { "family_name": "Marks", "given_name": "Michael", "clpid": "Marks-M" } ], "abstract": "Most amyloid precursor protein (APP)-based Alzheimer's models overexpress mutant human APP\nresulting in Abeta plaques. Yet the relative contribution of this elevated APP and the presence of\nplaques to neurodegeneration remains a big question. APP's role as a cargo-motor receptor for axonal\ntransport suggests that overexpression might lead to increased transport. Indeed we showed that\ntransport is increased in Down's syndrome and decreased in APP knockout mice. Hence transport may\nbe elevated in APP overexpressors and lead to either beneficial or deleterious consequences. Here we\nuse high field microMRI with Mn2+, an MR contrast agent useful as a track-tracer, to pose this cell\nbiological quest\nion within the whole living brains of wildtype and Alzheimer's model mice. Injection of\nMn2+ into the CA3 region of the hippocampus results in measurable transport over time. Application of\n3D unbiased whole brain image analysis detects all circuitry emanating from the hippocampus. By\ndriving APP Swe/Ind transgene expression with a tetracycline-sensitive promoter, APPSwe/Ind\nexpression can be decoupled from the presence of plaques with doxycycline (doxy). Three groups of\nmice were studied: group 'A' (no doxy, +plaques, +APP); group 'B' (doxy at 8 days before sacrifice,\n+plaques, no APP), and group 'C' (doxy prior to conception, and stopped 8 days before sacrifice, no\nplaques, +APP). Images were captured before and sequentionally after Mn2+ injection into CA\n3 (1, 7, 25\nhr). Images were aligned and analyzed by statistical parametric mapping to identify differential\naccumulation within the hippocampal projections. Histopathology revealed well-developed plaques in A\nand B, and Western blots showed human APP expressed five-fold over WT in in A and C. Our preliminary\nresults show increased transport in A and C, with APP Swe/Ind expression when compared with B,\nwhere expression is suppressed. Cholinergic neurons in the medial septal nucleus were decreased as\ndetermined by anti-ChAT staining in Group C (p=0.0006 by one-way ANOVA, n=15). In conclusion, the\neffects of elevated APP expression are separable from consequences of plaque, and each may.", "publisher": "Caltech Library", "publication_date": "2014-12" }, { "id": "authors:hf8jj-5qp84", "collection": "authors", "collection_id": "hf8jj-5qp84", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150504-140144268", "type": "conference_item", "title": "Developing a Model for Slow Hypoxic Injury and Vascular Degeneration in Amyloid Burdened Brains", "author": [ { "family_name": "Floruta", "given_name": "C. M.", "clpid": "Floruta-C-M" }, { "family_name": "Chaves", "given_name": "F. L.", "clpid": "Chaves-F-L" }, { "family_name": "Medina", "given_name": "C. S.", "clpid": "Medina-C-S" }, { "family_name": "Bearer", "given_name": "E. L.", "clpid": "Bearer-E-L" } ], "contributor": [ { "family_name": "Lippincott-Schwartz", "given_name": "Jennifer", "clpid": "Lippincott-Schwartz-J" }, { "family_name": "Marshall", "given_name": "Wallace", "clpid": "Marshall-W" }, { "family_name": "Marks", "given_name": "Michael", "clpid": "Marks-M" } ], "abstract": "The breakdown of neurovascular systems may play a crucial role in the pathogenesis of Alzheimer's\ndisease. However whether this breakdown initiates a degenerative mechanism or is the consequence of\nsome other deleterious process remains unknown. We examined hippocampal pathology in double\ntransgenic mice overexpressing a human mutant gene encoding the amyloid precursor protein\n(APPSwe/Ind) using a combination of histochemistry and stereologic techniques. Expression of\nAPPSwe/Ind in these mice is driven by a tetracycline-sensitive promoter. Tetracycline transcriptional\nactivator (tTA), the second transgene, is driven in turn by a CAM KIIa promoter that is only active in\nneurons. Thus this double transgenic construct allows us to control expression of APPSwe/Ind with\ndoxycycline. Utilizing this characteristic, we created three distinct experimental groups: A, display abeta\nplaque pathology and express APPSwe/Ind at time of sacrifice; B, display abeta plaque pathology but do\nnot express APPSwe/Ind at time of sacrifice; and C, do not display abeta plaque pathology but do\nexpress APPSwe/Ind at time of sacrifice. Stereologic investigation revealed decreased hippocampal\nvolume in groups A(n=5) and B(n=5) when compared to group C(n=5) and age-matched wildtype (n=9).", "publisher": "Caltech Library", "publication_date": "2014-12" } ]