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

ABSTRACT: Alzheimer's 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.

SUBMITTER: Yu W 

PROVIDER: S-EPMC3284124 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature