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P1‐107: In vivo analysis of APP functional domains
Author(s) -
Weyer Sascha W.,
Ring Sabine,
Filippov Mikhail,
Aydin Dorothee,
Bohlen Viola,
Vogt Miriam,
Gass Peter,
Caldwell John,
Mãller Ulrike C.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.694
Subject(s) - amyloid precursor protein , alpha secretase , ectodomain , biology , microbiology and biotechnology , knockout mouse , in vivo , presenilin , alzheimer's disease , neuroscience , medicine , gene , genetics , disease , receptor
which is -synuclein) within the surviving neurons of the substantia nigra and other brain regions. LRRK2 mutations are the most common cause of autosomal dominant PD and parkinsonism, and also occur in sporadic forms of the disease. Yet, many cases of what is typically thought of as a “synucleinopathy” have a higher than expected level of tau pathology compared to controls. The converse is true for Alzheimer’s disease (AD), where a four fold increase in Lewy bodies has been seen in sporadic cases of AD compared with controls. Additionally Novartis has recently patented LRRK2 polymorphisms as biomarkers for conversion of Mild Cognitive Impairment to AD. This led us to hypothesize that LRRK2 may represent a common link between tauopathies and synucleinopathies. Although direct interaction has not been established between tau and LRRK2, we decided to investigate the possibility of an interaction using transgenic mice with both inducible human P301L tau expressed in the forebrain and either mutant (G2019S) or wild-type human LRRK2. Methods: Mice have been analyzed by immunohistochemistry and Western blots for the impact of wild-type or mutant human LRRK2 on abnormal tau neuropathology and biochemical changes. Results: Inducible tau transgenic mice (rTg4510) develop pretangle pathology at 2.5M and mature tangles at 4M and 5.5M of age in the cortex and hippocampus, respectively. We have bred the rTg4510 line with BAC transgenic mice expressing either mutant (G2019S) or wild-type human LRRK2 and have aged them to these same timepoints. Initial analysis of one animal of each genotype at 4M and 5.5M indicates that overexpression of wild-type LRRK2 may delay the progression of tauopathy, resulting in fewer mature tangles and prolonged axonal localization of tau. Conclusions: Initial analysis of wild-type LRRK2 mice on the rTg4510 background suggests that LRRK2 may be protective against tauopathy. Data from larger aged cohorts as well as from the mutant LRRK2 mice on the rTg4510 background will be presented at the conference.