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-␤ (A␤) 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␤ 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␤ activation. In contrast, A␤ 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␤ levels are elevated in APP transgenic cultures and that inhibiting GSK-3␤ activity or use of phosphorylation-blocking tau mutations prevented A␤-induced toxicity of tau. FTDP-17 tau mutants are differentially affected by A␤. While R406W tau shows increased toxicity in the presence of A␤, no change is observed with P301L tau. While blocking NMDAR activity abolishes toxicity of both wt and R406W tau, the inhibition of GSK-3␤ only protects against toxicity of wt tau but not of R406W tau induced by A␤. Tau aggregation does not correlate with toxicity. We propose that A␤-induced spine pathology and tau-dependent neurodegeneration are mediated by divergent pathways downstream of NMDAR activation and suggest that A␤ affects wt and R406W tau toxicity by different pathways downstream of NMDAR activity.

Tau Accumulation Causes Mitochondrial Distribution Deficits in Neurons in a Mouse Model of Tauopathy and in Human Alzheimer's Disease Brain

“…(3) Other studies indicate that tau may interfere with signaling pathways, or molecules such as GSK3␤, thereby exerting more indirect control over transport processes. 20,49 Our data support tau-induced anterograde transport deficits as the general mechanism by which mitochondria become improperly distributed. The re-distribution of mitochondria following doxycycline treatment in the rTg4510, even in the continued presence of neuropil threads or NFT, suggests that the presence of aggregates of tau may not, in fact, serve as roadblocks, but rather that soluble tau species interfere with mitochondrial trafficking by some other means.…”

Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling

“…Previous studies show that overexpression of human mutant tau proteins impairs synapses (14,34). We found that overexpression of hTau significantly decreased spine density both in hippocampal neurons cultured for 12 d in vitro (div) (Fig.…”

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

“…Interestingly, alterations in spine structure and other plasticity-associated changes caused by tau misprocessing [236,237] may well involve the small amount of tau that is normally localized to the postsynaptic region in dendrites, as inducible P301L (rTg4510) mice show transient increases in behavioral plasticity before the onset of P301L tauinduced neurodegeneration [238], a finding that is consistent with the reduced MT binding of P301L tau, which presumably is therefore more likely to associate with perimembranous actin cytoskeleton rather than axonal MT.…”