BBS Faculty Member - Michael Wolfe

Michael Wolfe

Department of Neurology
Department of Biological Chemistry and Molecular Pharmacology

Brigham and Women's Hospital, Center for Neurologic Diseases
HIM Building, Room 754
4 Blackfan Circle
Boston, MA 02115
Tel: 617-525-5511
Fax: 617-525-5252
Lab Members: 2 postdoctoral fellows, 2 technicians, 1 undergraduate
Visit my lab page here.

The general theme of the lab is understanding the molecular basis of Alzheimer’s disease (AD) and related dementias and exploring new strategies for therapeutic intervention. One focus of the lab has been on gamma-secretase, a membrane-embedded protease that produces the amyloid beta-peptide (A-beta) implicated in the pathogenesis of AD. This protease also plays a variety of critical roles in biology. Small organic inhibitors were developed and used as tools to characterize and identify gamma-secretase. The lab discovered that gamma-secretase is a complex of four different integral membrane proteins, with presenilin as the catalytic component of an unusual aspartyl protease. Purification of the complex has allowed biochemical and structural characterization and a clearer understanding of how inhibitors and modulators interact with the enzyme. Ongoing projects include functional studies of the gamma-secretase complex, how these functions are altered by AD-causing presenilin mutations, and how these alterations may trigger AD pathogenesis.

Last Update: 8/6/2015


For a complete listing of publications click here.



Wolfe MS. g-Secretase as a target for Alzheimer’s disease. Adv Pharmacol. 2012; 64:127-53

Quintero-Monzon O, Martin MM, Fernandez MA; Cappello CA, Krzysiak AJ, Osenkowski P, Wolfe MS. Dissociation between processivity and total activity of gamma-secretase: implications for the mechanism of Alzheimer-causing presenilin mutations. Biochemistry 2011; 50(42): 9023-35.

Holmes O, Paturi S, Selkoe DJ, Wolfe MS. Pen-2 is essential for γ-secretase complex stability and trafficking but partially dispensable for endoproteolysis. Biochemistry. 2014; 53(27):4393-406.

Fernandez MA, Klutkowski JA, Freret T, Wolfe MS. Alzheimer Presenilin-1 Mutations Dramatically Reduce Trimming of Long Amyloid β-Peptides (Aβ) by γ-Secretase to Increase 42-to-40-Residue Aβ. J Biol Chem 2014; 289(45):31043-52.

© 2016 President and Fellows
of Harvard College