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Neurodegenerative diseases

New kinase targets for Alzheimer's disease

Nature Reviews Drug Discovery volume 12, page 739 (2013)Cite this article

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α-secretase-mediated cleavage of APP releases a soluble neuroprotective sAPPα fragment that hinders the formation of amyloid-β peptides. Reporting in Nature Medicine, Pietri et al. showed that the activity of tumour necrosis factor-converting enzyme (TACE), an enzyme that stimulates α-secretase, is reduced in patients with Alzheimer's disease and on the surface of neurons isolated from a mouse model of the disease. Furthermore, they found that 3-phosphoinositide-dependent protein kinase 1 (PDK1) activity is increased in both neurons affected by amyloid-β deposition and in the brains of patients. This triggers the internalization of TACE and impairs TACE-mediated α-secretase activity. When the authors inhibited PDK1 in three mouse models of Alzheimer's disease using the commercially available small-molecule inhibitor BX912 prior to the detection of plaque deposition, they found a decrease in the number of amyloid plaques and an increase in sAPPα levels compared with controls. Moreover, the treated mice showed improved performance in cognitive and memory tasks.

Interestingly, α-secretase also cleaves the cell surface prion protein PrPC, preventing its conversion to pathogenic prions (PrPSc). Similar to the results in neurons from mice with Alzheimer's disease-like pathology, an upregulation of PDK1 activity and a concomitant reduction in TACE activity was observed in prion-infected neurons. When the authors inhibited PDK1 (with BX912 or small interfering RNA) in prion-infected mice before the onset of symptoms, they observed reduced impairments in motor function, an attenuation of neuronal loss in the cerebellum and reduced PrPSc deposition. These results suggest that inhibition of PDK1 could be a useful strategy to inhibit disease progression in both Alzheimer's disease and prion disease.

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References

  1. Pietri, M. et al. PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer's diseases. Nature Med. 19, 1124–1131 (2013)

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  2. Ma, T. et al. Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits. Nature Neurosci. 16, 1299–1305 (2013)

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Authors
  1. Monica Hoyos Flight
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Flight, M. New kinase targets for Alzheimer's disease. Nat Rev Drug Discov 12, 739 (2013). https://doi.org/10.1038/nrd4132

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