A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of A on synapses and dendritic spines

作者：Yu Wendou; Polepalli Jai; Wagh Dhananjay; Rajadas Jayakumar; Malenka Robert; Lu Bingwei^*

来源：Human Molecular Genetics, 2012, 21(6): 1384-1390.

DOI：10.1093/hmg/ddr576

Alzheimers disease (AD) is the most common neurodegenerative disease and the leading cause of dementia in the elderly. Accumulating evidence supports soluble amyloid- (A) oligomers as the leading candidate for the causative agent in AD and synapses as the primary site of A oligomer action. However, the molecular and cellular mechanisms by which A oligomers cause synaptic dysfunction and cognitive impairments remain poorly understood. Using primary cultures of rat hippocampal neurons as a model system, we show that the partitioning defective-1 (PAR-1)/microtubule affinity-regulating kinase (MARK) family kinases act as critical mediators of A toxicity on synapses and dendritic spines. Overexpression of MARK4 led to tau hyperphosphorylation, reduced expression of synaptic markers, and loss of dendritic spines and synapses, phenotypes also observed after A treatment. Importantly, expression of a non-phosphorylatable form of tau with the PAR-1/MARK site mutated blocked the synaptic toxicity induced by MARK4 overexpression or A treatment. To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of A, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of A oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels. Our results reveal a critical role for PAR-1/MARK kinases in AD pathogenesis and suggest PAR-1/MARK inhibitors as potential therapeutics for AD and possibly other tauopathies where aberrant tau hyperphosphorylation is involved.

• 出版日期2012-3-15