Toxic tau: structural origins of tau aggregation in Alzheimer’s disease

Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.

Intraneuronal tau aggregation induces the integrated stress response in astrocytes

Progressive aggregation of tau protein in neurons is associated with neurodegeneration in tauopathies.Cell non-autonomous disease mechanisms in astrocytes may be important drivers of the disease process but remain largely elusive.Here,we studied cell type-specific responses to intraneuronal tau aggregation prior to neurodegeneration.To this end,we developed a fully human co-culture model of seed-independent intraneuronal tau pathology,which shows no neuron and synapse loss.Using high-content microscopy,we show that intraneuronal tau aggregation induces oxidative stress accompanied by activation of the integrated stress response specifically in astrocytes.This requires the direct co-culture with neurons and is not related to neurodegeneration or extracellular tau levels.Tau-directed antisense therapy reduced intraneuronal tau levels and aggregation and prevented the cell non-autonomous responses in astrocytes.These data identify the astrocytic integrated stress response as a novel disease mechanism activated by intraneuronal tau aggregation.In addition,our data provide the first evidence for the efficacy of tau-directed antisense therapy to target cell autonomous and cell non-autonomous disease pathways in a fully human model of tau pathology.