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Séminaire impromptu - Malcolm A LeissringThe ABCs of ABeta-Cleaving Proteases and Insulin-degrading enzyme in the pathogenesis and potential treatment of Alzheimer's disease

Abstract :

Titre : The ABCs of Aß-Cleaving Proteases and Insulin-degrading enzyme in the pathogenesis and potential treatment of Alzheimer's disease

Alzheimer’s disease (AD) is a progressive, age-related neurodegenerative disorder characterized by extracellular and intracellular deposition of the amyloid ß-protein (Aß).  The study of rare, familial forms of AD has shown that sustained elevations in the production of Aß (either all forms or specific pathogenic variants thereof) are sufficient to trigger the full spectrum of cognitive and histopathological features of the disease.  Emerging evidence suggests that impairments in the clearance of Aß, after it is produced, may underlie the vast majority of sporadic AD cases.  Aß-degrading proteases (AßDPs) in particular have emerged as particularly important mediators of Aß clearance.

 In this seminar, Dr. Leissring will provide a conceptual overview of the key role of AßDPs in the molecular pathogenesis and potential treatment of AD, including updates on the latest developments in this relatively poorly understood area.  Importantly, different AßDPs define distinct pools of Aß by virtue of their individual regional and subcellular localization profiles.  

Different pools of Aß, in turn, appear to contribute highly differentially to the pathogenesis of the disease.  Consequently, the study of individual Aß-degrading proteases promises to offer new insights into the mechanistic basis of AD pathogenesis, and—ultimately—may facilitate the development of effective methods for its prevention and/or treatment.

In the final part of this talk, Dr. Leissring will discuss the development of novel inhibitors of insulin-degrading enzyme (IDE), the principle protease involved in the catabolism of insulin.  Although IDE is one of the most widely studied AßDPs, emerging evidence indicates that IDE's role in modulating brain insulin may be considerably more important to the pathogenesis of AD than its role in regulating Aß levels.  
Indeed, boosting brain insulin signaling through the administration of intranasal insulin (itself a potent IDE inhibitor) has been shown to enhance memory in patients with prodromal AD and intranasal insulin is now being tested clinically.  These and other findings suggest that the novel IDE inhibitors developed by Dr. Leissring's group may have considerable therapeutic utility for as treatments for neurodegenerative disease.  

Moreover, IDE inhibitors have multiple other applications, particularly for the treatment and management of diabetes, which itself is a major risk factor for AD.  Together, this talk will provide novel conceptual insights into the pathogenesis of AD that might be exploited in the development of a new generation of therapeutics. 


The research of Malcolm A. Leissring, Ph.D., is focused on elucidating the molecular pathogenesis of Alzheimer's disease and other age-related neurodegenerative disorders, as well as the fundamental mechanisms underlying aging itself.The primary strengths of Dr. Leissring and his research group lie in discovering and characterizing novel drug targets, validating their suitability as therapies in vivo, and developing novel therapies and therapeutic approaches.
Toward these goals, they employ a wide variety of experimental methods ranging from the molecular to the organismal.

Selected publications

Optimization of Peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity.
Abdul-Hay SO, Lane AL, Caulfield TR, Claussin C, Bertrand J, Masson A, Choudhry S, Fauq AH, Maharvi GM, Leissring MA.
J Med Chem. 2013 Mar 28;56(6):2246-55. doi: 10.1021/jm301280p. Epub 2013 Mar 15.
PMID: 23437776 [PubMed - in process]

Identification of BACE2 as an avid ß-amyloid-degrading protease.
Abdul-Hay SO, Sahara T, McBride M, Kang D, Leissring MA.
Mol Neurodegener. 2012 Sep 17;7:46. doi: 10.1186/1750-1326-7-46.
PMID: 22986058 [PubMed - in process] Free PMC Article

Proteolytic degradation of amyloid β-protein.
Saido T, Leissring MA.
Cold Spring Harb Perspect Med. 2012 Jun;2(6):a006379. doi: 10.1101/cshperspect.a006379.
PMID: 22675659 [PubMed - in process] Free PMC Article

Characterization of insulin degrading enzyme and other amyloid-β degrading proteases in human serum: a role in Alzheimer's disease?
Liu Z, Zhu H, Fang GG, Walsh K, Mwamburi M, Wolozin B, Abdul-Hay SO, Ikezu T, Leissring MA, Qiu WQ.
J Alzheimers Dis. 2012;29(2):329-40. doi: 10.3233/JAD-2011-111472.
PMID: 22232014 [PubMed - indexed for MEDLINE]

Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance.
Abdul-Hay SO, Kang D, McBride M, Li L, Zhao J, Leissring MA.
PLoS One. 2011;6(6):e20818. doi: 10.1371/journal.pone.0020818. Epub 2011 Jun 9.
PMID: 21695259 [PubMed - indexed for MEDLINE] Free PMC Article
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Bio


Dr. Malcolm Leissring began his research career at the UC Berkeley in 1988 investigating fundamental mechanisms of learning and memory formation.  After receiving a Masters degree from San Francisco State University, Dr. Leissring sought to apply this knowledge to Alzheimer’s disease, electing to pursue his graduate studies in the laboratory of Dr. Frank LaFerla at UC Irvine, who has developed one of the most successful and widely studied Alzheimer’s mouse models in use today. Dr. Leissring conducted his post-doctoral research in the laboratory of Dr. Dennis Selkoe at Harvard Medical School, a world-renowned Alzheimer’s disease researcher.  In Dr. Selkoe’s laboratory, he carried out a seminal study showing that Alzheimer’s disease could be completely prevented in mice by proteases that break down the amyloid ß-protein (Aß), the primary constituent of the plaques that litter the brains of Alzheimer’s disease patients.  Dr. Leissring has continued pioneering work on Aß-degrading proteases, focusing in particular on the discovery and characterization of different proteases as well as the development of novel therapies targeting Aß catabolism.  To these ends, the Leissring laboratory uses a wide variety of techniques, including high-throughput compound screening, rational drug design, and cell and animal modeling.  Recently, Dr. Leissring developed the first potent inhibitors of insulin-degrading enzyme (IDE), a structurally unusual zinc-metalloprotease that is strongly implicated in the pathogenesis of both Alzheimer’s disease and diabetes.  Dr. Leissring current research is focused on using these novel IDE inhibitors both as probes to investigate the mechanistic links between Alzheimer’s and diabetes and as potential pharmacophores for the development of therapies aimed at enhancing insulin signaling.