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Tau Damages Neurons in Alzheimer's Disease by Disrupting Molecular Transport

Key findings

  • Researchers found that tau directly interacts with a nuclear pore complex (NPC) component, nucleoporin Nup98, which mislocalizes to the neuronal cytoplasm in brain tissue from patients from Alzheimer's disease (AD)
  • Nup98 triggers tau aggregation and accelerates tau fibrillization
  • Reducing soluble tau restored NPC impairment in mice
  • Reduction of Nup98 decreased NPC defects in neurons from transgenic mice expressing human AD tau
  • Strategies that prevent tau interactions with nucleoporins are promising therapeutic approaches for AD and other neurodegenerative diseases

Intracellular aggregation of tau into neurofibrillary tangles is a hallmark of Alzheimer's disease (AD) and is known to correlate with synapse loss and neurodegeneration. However, the mechanisms that drive tau aggregation are still unknown.

In Neuron, a team co-led by Bradley T. Hyman, MD, PhD, director of the Massachusetts Alzheimer Disease Research Center at Massachusetts General Hospital, reports multiple lines of in vitro and in vivo evidence that tau disrupts communication between the nucleus and cytoplasm of neurons. Specifically, it interacts with components of nuclear pore complexes (NPCs). Targeting those interactions could be a new therapeutic strategy for AD.

Background on NPCs

The researchers explain that NPCs, located on nuclear membranes, consist of multiple copies of 30 different proteins called nucleoporins (Nups). These molecular assemblies control the trafficking of RNA and larger proteins between the nucleoplasm and the cytoplasm.

The entry and exit of this "cargo" are controlled by a pair of proteins. During import, a molecule is released into the nucleus when its transport receptor interacts with intranuclear RanGTP. During export, a molecule is released into the cytoplasm upon hydrolysis of RanGTP to generate RanGDP. The nucleocytoplasmic gradient of RanGTP and RanGDP thus defines the directionality of nucleocytoplasmic transport.

Disruption of the Ran gradient can cause toxicity and cell death. In previous research, disrupted nucleocytoplasmic transport in neurons was detected in amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Huntington's disease and normal aging. However, the involvement of tau in these conditions, as well as its more general role in nucleocytoplasmic transport, had not been studied.

Nup98 Mislocalizes to the Neuronal Cytoplasm

The research team discovered that tau directly interacts with a nucleoporin called Nup98. They demonstrated this in vitro, in transgenic mice that express human tau and develop neurofibrillary tangles, and in tissue from patients with AD. Nup98 triggered tau aggregation and accelerated tau fibrillization.

The researchers also found evidence of cytoplasmic mislocalization of Nup98 in neurofibrillary tangles and neurons, as well as disrupted NPC distribution in the nuclear membrane. As a consequence, tau altered the import and export of proteins in neurons.

Reducing Soluble Tau Rescues Nucleocytoplasmic Transport and Nup98 Defects

In further experiments, Nup98 mislocalized to the cytoplasm and co-localized with tau in the transgenic mice but not in wild-type mice. To see if this is due to the interaction of Nup98 with soluble tau present in the soma, the researchers tested whether removing soluble tau and reducing tau aggregation could prevent Nup98 mislocalization and Ran gradient deficits.

The transgenic mice, which had pronounced tau but minor neurofibrillary tangles, were treated with doxycycline for six months. As expected, soluble tau was rapidly removed, and relatively few tangles were still present after treatment.

After treatment, untreated transgenic mice showed severe cytoplasmic Ran mislocalization. In contrast, in doxycycline-treated mice, nuclear localization of Ran had returned to control levels, and Nup98 reappeared in nuclear membranes, even in neurons that still contained tangles. Strikingly, it was possible to detect Nup98 in the tangles.

These findings confirm that soluble tau is mainly responsible for Nup98 displacement from NPCs and the nucleocytoplasmic transport deficits observed in the transgenic mice.

Reduction of Nup98 Decreases NPC Defects in Neurons

In a final set of experiments, the researchers obtained neurons from the PS19 transgenic mice, a second model that expresses human tau and develops neurofibrillary tangles. They treated the neurons with tau from control or AD brains (to increase the amount of aggregated tau in the soma), then knocked down levels of Nup98.

In neurons that received AD tau, the nuclear:cytoplasmic Ran ratio was reduced by ~ 50%. Anti-Nup98 treatment, which reduced Nup98 by about 70%, rescued the Ran ratio reduction almost completely. Thus, Nup98 directly contributes to tau-induced nucleocytoplasmic transport disruption and Ran mislocalization.

A Promising New Therapeutic Pathway

The researchers summarize their findings by proposing that accumulation of tau in the somatodendritic compartment increases tau concentration in the perinuclear space and enables abnormal interaction of tau with Nups. This, in turn, impairs the nucleocytoplasmic transport of molecules.

The researchers believe that targeting tau-Nup interactions could be a new therapeutic strategy for AD and similar neurodegenerative diseases.

Learn more about Mass General's Memory Disorders Division

Learn more about research in the Department of Neurology


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