15 May, 2013. Today, the MetLife Foundation honored Yueming Li and Lennart Mucke with its 2013 Awards for Medical Research in Alzheimer’s Disease. Li, who works at Memorial Sloan-Kettering Cancer Center in New York, garnered laurels for a decade’s worth of research on presenilin as the γ-secretase that cleaves amyloid-β (Aβ) from amyloid precursor protein (APP). Mucke, of the University of California, San Francisco, received accolades for his work revealing how Aβ co-opts tau and other proteins to disrupt neural communication. The MetLife annual award encourages the pursuit of new ideas in the study of AD. The scientists each receive a $200,000 research grant and a $50,000 personal check.

Li first identified presenilin as the catalytic core of γ-secretase in 2000 (see ARF related news story on Li et al., 2000). Some questioned if the enzyme was the true γ-secretase or just an adjunct. A decade later Li erased those doubts when he showed that presenilin, reconstituted alone in lipid membranes, cleaves γ-secretase substrates (see ARF related news story on Ahn et al., 2010). (Other scientists who were in the race to identify γ-secretase, Michael Wolfe and Dennis Selkoe of Brigham and Women’s Hospital, Boston, won this award in 2008 and 1986, respectively.) His group now focuses on ways to control γ-secretase activity as a potential AD therapy (e.g., see Shelton et al., 2009).

Mucke's work challenged the view that Aβ simply suppresses synaptic activity. He discovered that neural networks fire excessively in APP transgenic mice, resulting in epileptic-like seizures (see ARF related news story on Palop et al., 2007). The brain’s attempt to compensate then results in the downregulation of glutamate receptors (see ARF related news story on Cissé et al., 2011). Mucke then implicated tau, showing that halving the expression of this microtubule binding protein renders APP mice more resistant to overexcitation in the brain, quelling the toxic effects of Aβ (see ARF related news story on Roberson et al., 2007).—Amber Dance.

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References

News Citations

  1. γ-Secretase Sweepstakes: Presenilin Still in the Running
  2. Sole Perp—PS1 Alone Reconstitutes γ-Secretase Activity
  3. Do "Silent" Seizures Cause Network Dysfunction in AD?
  4. Aβ Downs EphB2 Kinase, Disrupts Glutamate Receptors
  5. APP Mice: Losing Tau Solves Their Memory Problems

Paper Citations

  1. . Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature. 2000 Jun 8;405(6787):689-94. PubMed.
  2. . Activation and intrinsic gamma-secretase activity of presenilin 1. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21435-40. PubMed.
  3. . Modulation of gamma-secretase specificity using small molecule allosteric inhibitors. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20228-33. PubMed.
  4. . Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6;55(5):697-711. PubMed.
  5. . Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature. 2011 Jan 6;469(7328):47-52. PubMed.
  6. . Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.

Further Reading

Papers

  1. . And four equals one: presenilin takes the gamma-secretase role by itself. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21236-7. PubMed.
  2. . Does epileptiform activity contribute to cognitive impairment in Alzheimer's disease?. Neuron. 2007 Sep 6;55(5):677-8. PubMed.
  3. . gamma-Secretase: characterization and implication for Alzheimer disease therapy. Neurobiol Aging. 2002 Nov-Dec;23(6):1023-30. PubMed.