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Luigi PuglielliM.D., Ph.D., Catholic University of Rome (Italy) |
Molecular aging of the brain and Alzheimer’s disease.
Alzheimer’s disease (AD) is the most common form of dementia, affecting up to 15 million individuals worldwide. The prevalence of AD increases progressively (without plateau) during aging, and aging itself is the single most important risk factor for AD. Because of the ongoing increase in life expectancy, the number of patients affected by AD is expected to rise to approx. 14 million in the United States and 50 million worldwide by 2050.
The two main histological hallmarks of AD are (i) the abnormal accumulation of amyloid beta-peptide (A-beta) in the form of senile (or amyloid) plaques and amyloid angiopathy, and (ii) the progressive and diffuse loss of neurons and synapses in the neocortex, hippocampus, and other subcortical regions of the brain.
Studies from several groups, including ours, are starting to delineate a complex number of biochemical pathways that can affect both A-beta generation and the ability of the brain to sustain/ generate synapses. Specifically, our group has identified a novel molecular pathway that connects the aging program mediated by the insulin-like growth factor 1 receptor (IGF1-R) to neurotrophin signaling and A-beta generation. IGF1-R is the common regulator of lifespan in all organisms. In fact, hyper-activation of IGF1-R leads to accelerated aging and short lifespan, whereas hypo-activation of IGF1-R leads to delayed aging and increased lifespan. Therefore, we have identified a molecular/biochemical pathway that links aging to AD, and that could explain the “AD-risk” associated with aging.
Both in vitro and in vivo experiments are now required to acquire more in-depth knowledge of this pathway and identify biochemical targets for the prevention of this devastating form of dementia.
Representative Publications
Huttunen, H.J., Puglielli, L., Ellis, B.C., MacKenzie Ingano, L.A., & Kovacs, D.M. (In Press) Novel N-terminal cleavage of APP precludes Ab generation in ACAT-defective AC29 cells. J. Mol. Neurosci.
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.
Ko, M.-H., & Puglielli, L. (2009). Two endoplasmic reticulum (ER)/ER golgi intermediate compartment-based lysine acetyltransferases post-translationally regulate BACE1 levels. J. Biol. Chem., 284, 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, 2008 April 2. [Epub ahead of print].
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. J. Biol. Chem., 282, 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. EMBO J., 25, 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. Biochem. J., 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. J. Clin. Invest., 115, 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, 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. J. Biol. Chem., 278, 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.
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