Divergent Pathways Mediate Spine Alterations and Cell Death Induced by Amyloid-beta, Wild-Type Tau, and R406W Tau
|ALZHEIMERS-DISEASE; CEREBRAL-CORTEX; CORTICAL-NEURONS; HIPPOCAMPAL-NEURONS; LONG-TERM DEPRESSION; NEURODEGENERATION; NEUROFIBRILLARY TANGLES; Neurosciences; Neurosciences & Neurology; PHOSPHORYLATION; PROTEIN; TRANSGENIC MICE
|JOURNAL OF NEUROSCIENCE
Alzheimer's disease is characterized by synaptic alterations and neurodegeneration. Histopathological hallmarks represent amyloid plaques composed of amyloid-beta(A beta) 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 A beta but not tau induces spine loss and shifts spine shape from mushroom to stubby through a mechanism involving NMDA receptor ( NMDAR), calcineurin, and GSK-3 beta activation. In contrast, A beta alone does not cause neurodegeneration but induces toxicity through phosphorylation of wild-type (wt) tau in an NMDAR-dependent pathway. We show that GSK-3 beta levels are elevated in APP transgenic cultures and that inhibiting GSK-3 beta activity or use of phosphorylation-blocking tau mutations prevented A beta-induced toxicity of tau. FTDP-17 tau mutants are differentially affected by A beta. While R406W tau shows increased toxicity in the presence of A beta, no change is observed with P301L tau. While blocking NMDAR activity abolishes toxicity of both wt and R406W tau, the inhibition of GSK-3 beta only protects against toxicity of wt tau but not of R406W tau induced by A beta. Tau aggregation does not correlate with toxicity. We propose that A beta-induced spine pathology and tau-dependent neurodegeneration are mediated by divergent pathways downstream of NMDAR activation and suggest that A beta affects wt and R406W tau toxicity by different pathways downstream of NMDAR activity.
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checked on Mar 2, 2024