Chromogranin B and Secretogranin II in Transgenic Mice Overexpressing Human APP751 with the London (V717I) and Swedish (K670M/N671L) Mutations and in Alzheimer Patients

Article type: Research Article

Authors: Willis, Michael^{a; b} | Prokesch, Manuela^c | Hutter-Paier, Birgit^c | Windisch, Manfred^c | Stridsberg, Mats^d | Mahata, Sushil K.^e | Kirchmair, Rudolf^f | Wietzorrek, Georg^b | Knaus, Hans-Günther^b | Jellinger, Kurt^g | Humpel, Christian^a | Marksteiner, Josef^{h; *}

Affiliations: [a] Department of General Psychiatry, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria | [b] Division of Molecular and Cellular Pharmacology, Medical University Innsbruck, Peter Mayr Strasse 1, 6020 Innsbruck, Austria | [c] JSW-Research, Forschungslabor GmbH, Rankengasse 28, 8020 Graz, Austria | [d] Department of Medical Sciences, Clinical Chemistry, University Hospital, SE-751 85 Uppsala, Sweden | [e] University of California, San Diego, USA | [f] Department of Internal Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria | [g] Institute of Clinical Neurobiology, Kenyongasse 18, 1070 Vienna, Austria | [h] Department of Psychiatry and Psychotherapy, Landeskrankenhaus Klagenfurt, A-9020 Klagenfurt, Austria

Correspondence: [*] Corresponding author: Josef Marksteiner, MD, Department of Psychiatry and Psychotherapy, Landeskrankenhaus Klagenfurt, A-9020 Klagenfurt, Austria. Tel.: +43 463 538 22970; E-mail: [email protected].

Abstract: Chromogranin B and secretogranin II are major soluble constituents of large dense core vesicles of presynaptic structures and have been found in neuritic plaques of Alzheimer patients. We examined the distribution and expression of these peptides in both transgenic mice over expressing human amyloid-β protein precursor APP751 with the London (V717I) and Swedish (K670M/N671L) mutations and in human post-mortem brain. In transgenic mice, the number of amyloid-β plaques and chromogranin immunopositive plaques increased from 6 to 12 months. About 60% of amyloid-β plaques were associated with chromogranin B and about 40% with secretogranin II. Chromogranin immunoreactivity appeared mainly as swollen dystrophic neurites. Neither synaptophysin- nor glial fibrillary acidic protein- immunoreactivity was expressed in chromogranin immunoreactive structures at any timepoint. Density of chromogranin peptides in hippocampal structures did not change in transgenic animals at any timepoint, even though animals had a poorer performance in the Morris water maze task. In conclusion, our findings in transgenic animals partly resembled findings in Alzheimer patients. Chromogranin peptides were associated with amyloid-β plaques, but were not reduced in specific brain areas as previously reported by our group. Therefore specific changes of chromogranin peptides observed in Alzheimer patients can be related to amyloid-β pathology only.

Keywords: Alphabetize: amyloid-beta, chromogranin B, large dense core vesicles, secretogranin II, transgenic

DOI: 10.3233/JAD-2008-13202

Journal: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 123-135, 2008