Luigi Puglielli, MD, PhD

Portrait of Luigi Puglielli, MD, PhD
Associate Professor
D4247 VAH
2500 Overlook Terrace
Madison, WI 53792
(608) 280-7000
Focus Groups: 
MD, Catholic University, Rome, Italy
PhD, Catholic University, Rome, Italy
Research Summary: 
We are interested in (1) the molecular mechanisms responsible for the cognitive decline that accompanies aging and (2) the molecular pathogenesis of neurodegenerative diseases.
Research Detail: 

Our broad research interests focus on the molecular mechanisms that are responsible for the cognitive loss that accompanies aging and the neurodegeneration that characterizes Alzheimer's disease. Our research uses multidisciplinary approaches on in vitro, ex vivo and in vivo models. Such approaches include biochemical, cellular and molecular techniques, as well as electrophysiological, cognitive/behavioral, and structural analysis.

Active projects include:

  1. Molecular mechanisms of cognitive loss during aging and Alzheimer's disease neuropathology. We have identified a novel link between aging and Alzheimer's disease, which, when hyperactive, results in synaptic and cognitive deficits, and in severe degeneration of memory-forming and -retrieving areas of the brain. The molecular mechanisms involved in these events are being actively sought.
  2. Post-translational regulation of membrane proteins. We have identified a novel form of post-translational regulation of membrane proteins that acts in the early secretory pathway. These findings are particularly important as they can shed light in several types of neurodegenerative diseases. New relevant animal models are being generated to extend our findings.
  3. Drug discovery for the prevention of Alzheimer's disease. We have identified compounds that block some of the early biochemical events involved in the pathogenesis of Alzheimer's disease. They target the ER-based lysine acetylation machinery identified in our laboratory. Mechanisms of action as well as therapeutic potential are being actively studied.
Selected Publications: 
Peng Y, Li M, Clarkson BD, Pehar M, Lao PJ, Hillmer AT, Barnhart TE, Christian BT, Mitchell HA, Bendlin BB, Sandor M, Puglielli L. (2014). Deficient import of acetyl-CoA into the ER lumen causes neurodegeneration and propensity to infections, inflammation, and cancer. J Neurosci 34: 6772-89.
Pehar M, Ko MH, Li M, Scrable H, Puglielli L. (2014). p44, the “longevity-assurance” isoform of p53, regulates tau phosphorylation and is activated in an age-dependent fashion. Aging Cell 13: 449-456.
Pehar, M., and Puglielli, L. (2013). Lysine acetylation in the lumen of the ER: a novel and essential function under the control of the UPR. Biochim Biophys Acta 1833:686-697.
Pehar M, Jonas MC, Hare T, Puglielli L. (2012). SLC33A1/AT-1 regulates the induction of autophagy down-stream of IRE1/XBP1. J Biol Chem 287:29921-29930.
Pehar, M., Lehnus, M., Karst, A., & Puglielli, L. (2012). Proteomic Assessment Shows That Many Endoplasmic Reticulum (ER)-resident Proteins Are Targeted by N-Lysine Acetylation in the Lumen of the Organelle and Predicts Broad Biological Impact. Journal of Biological Chemistry, 287(27), 22436-22440.
Ding, Y., Ko, M.H., Pehar, M., Kotch, F., Peters, N.R., Luo, Y., Salamat, S.M., & Puglielli, L. (2012). Biochemical inhibition of the acetyltransferases ATase1 and ATase2 reduces β-secretase (BACE1) levels and Aβ generation. Journal of Biological Chemistry 287(11), 8424-8433.
Bendlin, B.B., Carlsson, C.M., Gleason, C.E., Johnson, S.C., Sodhi, A., Gallagher, C.L., Puglielli, L., Engelman, C.D., Ries, M.L., Xu, G., Wharton, W., & Asthana, S. (2010). Midlife predictors of Alzheimer's disease. Maturitas, 65(2), 131-137.
Jonas, M.C., Pehar, M., & Puglielli, L. (2010). AT-1 is the ER membrane acetyl-CoA transporter and is essential for cell viability. Journal of Cell Science, 123(19), 3378-3388.
Pehar, M., O'Riordan, K.J., Burns-Cusato, M., Andrzejewski, M.E., del Alcazar, C.G., Burger, C., Scrable, H., & Puglielli, L. (2010). Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death. Aging Cell, 9(2), 174-190.
Carlsson, C.M., Gleason, C.E., Puglielli, L., & Asthana, S. (2009). Dementia including Alzheimer’s disease. In J. Halter, J. Ouslander, M. Tinnetti, S. Studenski, & S. Asthana (Eds.), Hazzard’s Geriatric Medicine and Gerontology (6th ed.). New York: McGraw-Hill Professional.
Huttunen, H.J., Puglielli, L., Ellis, B.C., MacKenzie Ingano, L.A., & Kovacs, D.M. (2009). Novel N-terminal cleavage of APP precludes Aβ generation in ACAT-defective AC29 cells. J. Mol. Neurosci., 37(1), 6-15.
Ko, M.H., & Puglielli, L. (2009). Two ER/ERGIC-based lysine acetyltransferases post-translationally regulate BACE1 levels. Journal of Biological Chemistry, 284(4), 2482-2492.
Puglielli, L. (2008). Aging of the brain, neurotrophin signaling, and Alzheimer’s disease: is IGF1-R the common culprit? Neurobiology of Aging, 29(6), 795-811.
Jonas, M.C., Costantini, C., & Puglielli, L. (2008). PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep., 9, 916-922.
Li, H., Costantini, C., Scrable, H., Weindruch, R., & Puglielli, L. (2008). Egr-1 and Hipk2 are required for the TrkA to p75NTR switch that occurs downstream of IGF1-R. Neurobiology of Aging, 30(12), 2010-2020.
Carlsson, C.M., Gleason, C.E., Hess, T.M., Moreland, K.A., Blazel, H.M., Koscik, R.L., Schreiber, N.T.N., Johnson, S.C., Atwood, C.S., Puglielli, L., Hermann, B.P., McBride, P.E., Stein, J.H., Sager, M.A., & Asthana, S. (2008). Effects of simvastatin on cerebrospinal fluid biomarkers and cognition in middle-aged adults at risk for Alzheimers disease. Journal of Alzheimers Disease, 13(2), 187-97.
Costantini, C., Ko, M.H., Jonas, M.C., & Puglielli, L. (2007). A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1. Biochem. J., 407, 383-395.
Ko, M-H., & Puglielli, L. (2007). The sterol carrier protein SCP-x/pro-SCP-2 gene has transcriptional activity and regulates the Alzheimer’s disease g-secretase. Journal of Biological Chemistry, 282(27), 19742-19752.
Costantini, C., Scrable, H., & Puglielli, L. (2006). An aging pathway controls the TrkA to p75 neurotrophin receptor switch and amyloid beta-peptide generation in neurons. The European Molecular Biology Organization Journal, 25(9), 1997-2006.
Costantini, C., Kolasani, R.M.K., & Puglielli, L. (2005). Ceramide and cholesterol: possible connections between normal aging of the brain and Alzheimer’s disease. Just hypotheses or molecular pathways to be identified? Alzheimer’s & Dementia, 1, 43-50.
Costantini, C., Weindruch, R., Della Valle, G., & Puglielli, L. (2005). A TrkA to p75NTR molecular switch activates amyloid beta-peptide generation during aging. Biochemical Journal, 391, 59-67.
Puglielli, L., Friedlich, A.L., Setchell, K.D.R., Nagano, S., Opazo C., Cherny R.A., Barnham, K.J., Wade, J.D., Melov, S., Kovacs, D.M., & Bush, A.I. (2005). Alzheimer’s disease beta-amyloid activity mimics cholesterol oxidase. Journal of Clinical Investigation, 115(9), 2556-2563.
Hutter-Paier, B., Huttunen, H.J., Puglielli, L., Eckman, C.B., Kim, D.Y., Hofmeister, A., Moir, R.D., Dominitz, S.B., Frosch, M.P., Windisch, M., & Kovacs, D.M. (2004). The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer’s disease. Neuron, 44(2), 227-238.
Puglielli, L., Ellis, B.C., Ingano, L.A., & Kovacs, D.M. (2004). Role of acyl-coenzyme a: cholesterol acyltransferase activity in the processing of the amyloid precursor protein. J. Mol. Neurosci., 24, 93-96.
Puglielli, L., Ellis, B.C., Saunders, A.J., & Kovacs, D.M. (2003). Ceramide stabilizes BACE1 and promotes amyloid beta-peptide biogenesis. Journal of Biological Chemistry, 278(22), 19777-19783.
Puglielli, L., Tanzi, R.E., & Kovacs, D.M. (2003). Alzheimer’s disease: the cholesterol connection. Nature Neuroscience, 6, 345-351.
Puglielli, L., Konopka, G., Pack-Chung, E., MacKenzie Ingano, L.A., Berezovska, O., Hymam, B.T., Chang, T.Y., Tanzi, R.E., & Kovacs, D.M. (2001). Acyl coenzyme-A:cholesterol acyltransferase (ACAT) modulates the generation of the amyloid beta-peptide. Nature Cell Biology, 3, 905-912.