The characteristic neuropathological deposits identified in Alzheimer's disease (AD) are the extracellular amyloid beta (A?) plaques and intracellular tau tangles. Neurofibrillary degeneration in the absence of ?- amyloid, is also seen in several tauopathies such as Guam parkinsonism dementia complex, dementia pugilistica, corticobasal degeneration, Pick's disease, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and progressive supranuclear palsy. It is well established that hyperphosphorylation of tau is responsible for the neurofibrillary lesions found in these conditions, while A?, a cleavage product of the amyloid precursor protein (APP), is a main constituent of the plaques. The interrelationship between hyperphosphorylated tau and A? has been well studied, however, new functions for tau in signaling and cytoskeletal organization have emerged that challenge previously held paradigms (Morris et al., 2011). Studies have also shown that reduction in wild-type tau prevents A?-dependent behavioral and cognitive deficits (Roberson et al., 2007), suggesting that therapeutic interventions that alter the levels of tau may be beneficial. The transcription factor specificity protein 1 (Sp1) is essential for the regulationof the tau gene and its cyclin dependent kinase 5 (CDK5). Studies from our lab have provided convincing evidence that either silencing of the Sp1 gene using small interfering RNA (Basha et al., 2005) or treatment of animals with tolfenamic acid lowers the expression of AD-related Sp1 target genes (Adwan et al., 2011). Preliminary data from our lab have also demonstrated that tolfenamic acid can reduce tau protein and mRNA levels in animal models. Tolfenamic acid has been approved for human use in migraine headaches in Europe. Therefore, it affords potential as a """"""""repurposed drug"""""""" for rapid development with limited concerns about its toxicity in humans. In this proposal, we intend to examine if tolfenamic acid can interfere with the regulation of the tau gene and alter the levels of its product and examine the impact of such alterations on the phosphorylation of tau and its immunohistopathological distribution in htau transgenic mice.
The number of people suffering from Alzheimer's disease (AD) is expected to increase exponentially in the coming decades. AD is the third most expensive disease in the US estimated to cost the economy about $100 billion annually. In addition to AD many other neurodegenerative diseases contain deposits of the protein tau. These tauopathies impact the health of many individuals and lead to dementia. There are no approved drugs that modify the pathology associated with tau or decrease other symptoms associated with these diseases. We have discovered that tolfenamic acid lowers the levels of proteins associated with AD pathogenesis. Tolfenamic acid is approved in Europe as an anti-migraine drug. We would like to repurpose this drug for the treatment of AD and taupathies. Here we plan to perform exploratory studies that will provide some proof that tolfenamic acid can lower the levels of the protein tau that is involved in tangles and serve a role as a candidate for a disease-modifying drug.
|Adwan, Lina; Subaiea, Gehad M; Basha, Riyaz et al. (2015) Tolfenamic acid reduces tau and CDK5 levels: implications for dementia and tauopathies. J Neurochem 133:266-72|
|Adwan, Lina; Subaiea, Gehad M; Zawia, Nasser H (2014) Tolfenamic acid downregulates BACE1 and protects against lead-induced upregulation of Alzheimer's disease related biomarkers. Neuropharmacology 79:596-602|
|Bihaqi, Syed Waseem; Bahmani, Azadeh; Adem, Abdu et al. (2014) Infantile postnatal exposure to lead (Pb) enhances tau expression in the cerebral cortex of aged mice: relevance to AD. Neurotoxicology 44:114-20|
|Bihaqi, Syed Waseem; Zawia, Nasser H (2013) Enhanced taupathy and AD-like pathology in aged primate brains decades after infantile exposure to lead (Pb). Neurotoxicology 39:95-101|