Role of Toll like receptors (TLR’s) in neurodegeneration. Involvement of BAG2 in toxic tau degradation

Nome do Pesquisador: Daniel Carneiro Carrettiero

Agência de fomento: CNPq

Vigência: dez/14 à dez/17

Resumo: Alzheimer’s disease (AD) is a neurodegenerative disorder caused by progressive loss of synapses and neurons, characterized by memory dysfunction and global cognitive impairment. The pathological hallmarks for AD are extracellular senile plaques of amyloid-β-peptide (Aβ) and intracellular neurofibrillary tangles (NFTs) of hyper-phosphorylated tau protein. AD is among one of the disorders of tauopathy where tau is a family of neuronal phosphoproteins that modulate the stability and dynamics of the microtubule network. However in AD brain, tau is hyperphosphorylated and does not bind to the microtubule and aggregates into paired helical filaments (PHFs) and NFTs. Currently, there is increasing evidence that innate immune system is involved in neuroinflammatory process of neurodegenrative disease such as AD. The innate immune system senses the invasion of pathogens and tissue injury through Toll-like recpetors (TLRs). Cellular activation of TLRs mediates activation of transcription factors such as NF-κB and subsequent production of inflammatory cytokines, interferon-α or –β. A recent study has reported the involvement of TLR3 in SH-SY5Y neuroblastoma cells showing increased hyperphosphorylation of tau through activation of Jun N Terminal Kinase (JNK) and p38- mitogen activated protein kinase (p38 MAPK). In addition to this, LPS activated TLR4 mediates extensive neuronal cell death in cell cultures due to hyperphosphorylation of tau. Further more, neurons from TLR4 mutant mice exhibited reduced JNK and casapase-3 activation and were protected against apoptosis induced by LPS. These observations suggest the involment of TLR3 and TLR4 in hyperphosphorylation of tau. The accumulation of ubiquitinated tau proteins in cells could arise due to a failure on tau degradation process involving proteasome using co-chaperones. On the other hand, the co-chaperone BAG2 can degrade phosphorylated tau in an ubiquitin-independent manner and promote cell survival. Hence the present study will investigate the role of TLR3 and TLR4 in modulation of BAG2 promoted tau.

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