Cofilin Suppresses Tau-Induced Defects in Dense-Core Granule Formation and Aβ-Induced Neurodegeneration

Abstract

Intracellular neurofibrillary tangles formed from hyperphosphorylated tau and extracellular amyloid plaques containing aggregated Aβ-peptides, specific cleavage products of the Amyloid Precursor Protein (APP), are the primary histopathological hallmarks of Alzheimer’s Disease (AD), the leading cause of dementia in humans. However, the initiating steps that lead to these pathologies and early neurodegeneration, and the mechanisms by which tau- and Aβ-induced effects might be linked remain unclear. Using the prostate-like secondary cell (SC) in Drosophila, we recently showed that Aβ modulates normal APP- and membrane-associated protein aggregation in the dense-core granule (DCG) compartments of the regulated secretory pathway by interfering with subsequent membrane:DCG dissociation. This disrupts endolysosomal trafficking and propagates the resulting endolysosomal defects to other cells that endocytose the secreted abnormal DCG proteins. Here we show that overexpressing human tau also disrupts DCG aggregation and membrane:DCG dissociation inside SC secretory compartments, leading to increased endolysosomal targeting of these compartments. In a genetic screen, we find that knockdown of cofilin, which encodes an actin-severing protein required for dynamic remodelling of microfilaments, generates a similar phenotype. Consistent with this, overexpression of Cofilin, which is known to suppress tau-induced neurodegeneration in flies, reduces tau-induced DCG defects in SCs. Indeed, we find that Cofilin overexpression also suppresses Aβ-induced degeneration in the fly eye. We conclude that membrane:DCG aggregate dissociation in DCG compartments is disrupted by both tau- and Aβ-induced genetic changes that are relevant to AD, and this partially involves inhibition of actin cytoskeleton dynamics. Increasing actin remodelling activity can suppress neurodegeneration induced by both tau and Aβ, suggesting that this process provides an important functional link between them that might be targeted therapeutically.