P2‐219: ADF/cofilin‐actin rods and synaptic loss in Alzheimer's disease

Striated neuropil threads, containing ∼20 nm paired helical filaments (PHF) of tau, account for 85% of the tau pathology in Alzheimer disease (AD) brain. Tandem arrays (striations) of rod-like cofilin immunostaining are also found in AD brain, where bundles of ∼10 nm filaments, corresponding to cofilin-saturated actin, also have been observed. Cofilin-actin rods are induced in axons and dendrites of cultured rat hippocampal or cortical neurons or organotypic hippocampal slices subjected to physiological stresses such as excitotoxic glutamate, reactive oxygen species (ROS), Aβ oligomers, or hypoxia/ischemia. Rods also form in response to F-actin disruption by latrunculins. Rods block intra-neurite transport, which subsequently leads to distal synaptic loss. Some rod-inducing stimuli enhance Aβ secretion 2-3 fold, providing a potential feed-forward mechanism for enhancing Aβ-mediated degeneration. Cofilin-actin rods are necessary for and co-localize with hyperphosphorylated isoforms of tau that occur in striated neuropil threads, suggesting rods mediate tau reorganization and PHF assembly. Rods isolated from rat cortical neurons contain ADF/cofilin and actin in a 1:1 ratio, suggesting that they contain actin filaments saturated with ADF/cofilin. Similar structures can be formed in vitro with purified ADF or cofilin and actin. Rod formation in vivo is blocked by stabilizing F-actin with jasplakinoloide or by inhibiting actin assembly with cytochalasin D, implying rods form by reassembly of ADF/cofilin-actin. Rod formation in vivo is inhibited by maintaining ADF/cofilin in an inactive (phosphorylated) form by overexpressing active LIM kinase. Rod formation in response to stress is exacerbated by overexpressing slingshot-1L or chronophin, i.e. ADF/cofilin phosphatases. In organotypic hippocampal slices, rod formation downstream of Aβ is particularly focused within neurons of the dentate gyrus and mossy fiber tract. Secreted Aβ from the 7PA2 CHO cell line is ∼5000 fold more potent in inducing rods than is traditionally prepared synthetic Aβ oligomer (200 pM vs 1 μM). Together these data suggest that cofilin-actin rods play a major role in the development of both Aβ accumulation and tau AD pathology and could help explain the synaptic loss without cell death that occurs in the early phases of AD and other neurodegenerative diseases.