Editors' ChoiceAlzheimer’s Disease

The hunt for a cure for Alzheimer’s disease receives a timely boost

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Science Translational Medicine  11 Sep 2019:
Vol. 11, Issue 509, eaaz0311
DOI: 10.1126/scitranslmed.aaz0311

Abstract

Therapeutic strategy based on inhibition of tau hyperphosphorylation performs better than glutamate uptake by astrocytes in a mouse model.

No treatments for Alzheimer’s disease have been approved since 2003. For much of these barren years, drug hunters largely focused on identifying agents that target either β-amyloid, tau protein, gliotransmitters or neurotransmitters. More recently, aided by a deeper understanding of the pathophysiology of the disease, the search for new therapies has converged upon two strategies. The first involves inhibition of tau hyperphosphorylation by glycogen synthase kinase 3β (GSK3β), which can be achieved by preferentially phosphorylating the kinase at the serine 9. The second strategy involves restoration of synaptic activity through enhancement of the rate of glutamate uptake from the tripartite synaptic cleft by astrocytes. Both strategies have their merits, and debates about the comparative superiority of either strategy have been raging. A recent work by Foster et al. compared the two strategies in transgenic mice expressing a microtubule-associated form of tau in neurons in the forebrain (Tau mice). They first evaluated a pyridazine derivative for its ability to facilitate preferential phosphorylation of GSK3β at serine 9 and noticed that transgenic mice that received a daily dosage of 10 mg/kg exhibited no learning and memory reduction for as long as two months following treatment initiation. Moreover, the treatment also preserved the postsynaptic density in the hippocampi. Although efficacy of the drug started to wane as the disease progressed to an advanced state, the cognitive functions of the treated mice remained superior to those of untreated mice. Moreover, the positive effects of the drug were noticeable for close to a month following cessation of treatment. To test whether enhancement of glutamate uptake by the astrocytes can restore synaptic activity, Foster and colleagues crossed Tau mice with mice overexpressing the excitatory amino acid transporter 2 (EAAT2) and assessed cognition and postsynaptic density in each of the three species. EAAT2 is responsible for glutamate uptake by the astrocytes. In a strange twist, they observed that expression of EAAT2 in the Tau mice was higher than both the crossed and the EAAT2 overexpressing mice, in that order, and EAAT2 expression was negatively correlated with memory performance and postsynaptic density. The team also observed that the Tau mice that were only treated with the pyridazine derivative exhibited better outcomes than crossed mice receiving the same treatment. Further investigations are clearly warranted to elucidate the true mechanisms of action of the two approaches. Nevertheless, targeting tau hyperphosphorylation appears to produce superior outcomes over glutamate clearance from the synaptic cleft. It will be interesting to see how these impressive results translate to human models of the disease. Those in the field often joke that Alzheimer’s disease has been cured in mice. It’s the human form of the disease that continues to evade drug hunters.

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