Divergent pathways mediate spine alterations and cell death induced by amyloid-β, wild-type tau, and R406W tau

Abstract

Alzheimer's disease is characterized by synaptic alterations and neurodegeneration. Histopathological hallmarks represent amyloid plaques composed of amyloid-β (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau. To determine whether synaptic changes and neurodegeneration share common pathways, we established an ex vivo model using organotypic hippocampal slice cultures from amyloid precursor protein transgenic mice combined with virus-mediated expression of EGFP-tagged tau constructs. Confocal high-resolution imaging, algorithm-based evaluation of spines, and live imaging were used to determine spine changes and neurodegeneration. We report that Aβ but not tau induces spine loss and shifts spine shape from mushroom to stubby through a mechanism involving NMDA receptor (NMDAR), calcineurin, and GSK-3β activation. In contrast, Aβ alone does not cause neurodegeneration but induces toxicity through phosphorylation of wild-type (wt) tau in an NMDAR-dependent pathway. We show that GSK-3β levels are elevated in APP transgenic cultures and that inhibiting GSK-3β activity or use of phosphorylation-blocking tau mutations prevented Aβ-induced toxicity of tau. FTDP-17 tau mutants are differentially affected by Aβ. While R406W tau shows increased toxicity in the presence of Aβ, no change is observed with P301L tau. While blocking NMDAR activity abolishes toxicity of both wt and R406W tau, the inhibition of GSK-3β only protects against toxicity of wt tau but not of R406W tau induced by Aβ. Tau aggregation does not correlate with toxicity. We propose that Aβ-induced spine pathology and tau-dependent neurodegeneration are mediated by divergent pathways downstream of NMDAR activation and suggest that Aβ affects wt and R406W tau toxicity by different pathways downstream of NMDAR activity. Copyright © 2009 Society for Neuroscience.