Year: 2012
Type: article
Abstract: Tauopathies are neurodegenerative disorders characterized by the accumulation of intracellular neurofibrillary tangles (NFTs) composed of abnormally phosphorylated tau. Mutations in the tau gene, MAPT, result in Frontotemporal dementia with Parkinsonism linked to chromosome 17 and interestingly, the MAPT H1 haplotype is a risk factor for both a subset of tauopathies and sporadic Parkinson's disease (PD). Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal dominant Parkinsonism and are implicated in sporadic PD. Carriers of the most frequent PD-specific mutation, G2019S, have pleomorphic pathology that includes NFTs; incomplete penetrance indicates that other genetic or environmental factors are important for G2019S LRRK2 disease. This suggests that LRRK2 and tau may interact in overlapping pathological cascades, a link that has not been fully tested in vivo. We have created the first LRRK2 and tau double transgenic mice by crossing BAC WT and G2019S LRRK2 mice with the rTg4510 model with inducible human tau overexpression. Recently we have found that adult induction of tau in the rTg4510 mice markedly slows the normal time course of pathology, which includes NFT formation and neuronal loss. Exploiting this, G2019S LRRK2 was continuously expressed while human tau was co-expressed starting at 5.5M to test if mutant Lrrk2 predisposes adult neurons to tauopathy. Pathology assessment includes immunohistochemical analysis of neurodegeneration and tau protein biochemistry. All mice have been harvested and pathological analysis is currently underway. Preliminary western blot results show that after 8.25M of adult expression there is an abnormal increase in tau of normal molecular weight (∼50kDa) in the sarkosyl-insoluble fraction and the initial appearance of 64kDa tau, which is the biochemical equivalent of NFTs. At the time of the conference, full immunohistochemical and biochemical data will be presented and will include data from littermates that constitutively express G2019S LRRK2 and human tau. The finding of the biochemical equivalent of NFTs after 8.25M of adult expression indicates that the normal pathological course of rTg4510 is significantly delayed. This provides a primed system to evaluate the potential of mutant LRRK2 to predispose adult neurons to tauopathy. Full conclusions will be discussed at the meeting.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2074334386