Amyloid beta-mediated cell death of cultured hippocampal neurons reveals extensive Tau fragmentation without increased full-length tau phosphorylation.

ABSTRACT: A variety of genetic and biochemical evidence suggests that amyloid ? (A?) oligomers promote downstream errors in Tau action, in turn inducing neuronal dysfunction and cell death in Alzheimer and related dementias. To better understand molecular mechanisms involved in A?-mediated neuronal cell death, we have treated primary rat hippocampal cultures with A? oligomers and examined the resulting cellular changes occurring before and during the induction of cell death with a focus on altered Tau biochemistry. The most rapid neuronal responses upon A? administration are activation of caspase 3/7 and calpain proteases. A? also appears to reduce Akt and Erk1/2 kinase activities while increasing GSK3? and Cdk5 activities. Shortly thereafter, substantial Tau degradation begins, generating relatively stable Tau fragments. Only a very small fraction of full-length Tau remains intact after 4 h of A? treatment. In conflict with expectations based on suggested increases of GSK3? and Cdk5 activities, A? does not cause any major increases in phosphorylation of full-length Tau as assayed by immunoblotting one-dimensional gels with 11 independent site- and phospho-specific anti-Tau antibodies as well as by immunoblotting two-dimensional gels probed with a pan-Tau antibody. There are, however, subtle and transient increases in Tau phosphorylation at 3-4 specific sites before its degradation. Taken together, these data are consistent with the notion that A?-mediated neuronal cell death involves the loss of full-length Tau and/or the generation of toxic fragments but does not involve or require hyperphosphorylation of full-length Tau.

SUBMITTER: Reifert J 

PROVIDER: S-EPMC3121465 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature