title: Increased tau phosphorylation and tau truncation, and decreased synaptophysin levels in mutant BRI2/tau transgenic mice.
abstract: Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease caused by a 10-nucleotide duplication-insertion in the BRI(2) gene. FDD is clinically characterized by loss of vision, hearing impairment, cerebellar ataxia and dementia. The main neuropathologic findings in FDD are the deposition of Danish amyloid (ADan) and the presence of neurofibrillary tangles (NFTs). Here we investigated tau accumulation and truncation in double transgenic (Tg-FDD-Tau) mice generated by crossing transgenic mice expressing human Danish mutant BRI(2) (Tg-FDD) with mice expressing human 4-repeat mutant Tau-P301S (Tg-Tau). Compared to Tg-Tau mice, we observed a significant enhancement of tau deposition in Tg-FDD-Tau mice. In addition, a significant increase in tau cleaved at aspartic acid (Asp) 421 was observed in Tg-FDD-Tau mice. Tg-FDD-Tau mice also showed a significant decrease in synaptophysin levels, occurring before widespread deposition of fibrillar ADan and tau can be observed. Thus, the presence of soluble ADan/mutant BRI(2) can lead to significant changes in tau metabolism and synaptic dysfunction. Our data provide new in vivo insights into the pathogenesis of FDD and the pathogenic pathway(s) by which amyloidogenic peptides, regardless of their primary amino acid sequence, can cause neurodegeneration.
authors: Department of Pathology and Laboratory Medicine and Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America. hjgarrin@iupui.edu
authors: Holly J
authors: HJ
authors: Garringer
authors: Jill
authors: J
authors: Murrell
authors: Neeraja
authors: N
authors: Sammeta
authors: Anita
authors: A
authors: Gnezda
authors: Bernardino
authors: B
authors: Ghetti
authors: Ruben
authors: R
authors: Vidal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D002386:Cataract / Q000235:genetics / Q000378:metabolism; D002524:Cerebellar Ataxia / Q000235:genetics / Q000378:metabolism; D003638:Deafness / Q000235:genetics / Q000378:metabolism; D003704:Dementia / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016708:Synaptophysin / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D016708:Synaptophysin; D016875:tau Proteins; D001224:Aspartic Acid