Contact Information

Biography

Assistant Professor of Medicine with primary appointment in the Section of Geriatrics and Gerontology.

Other Local Affiliation: Geriatric Research, Education and Clinical Center (GRECC) at the Vm. S. Middleton VA Hospital; The Memory Research Program; The Institute on Aging; The Program in Cellular and Molecular Biology; The Wisconsin Alzheimer's Institute.

Education/Training

MD, PhD, 1989/1993 Catholic University of Rome (Italy)

Post Doctoral Training 1993-1995, Catholic University of Chile (Santiago, Chile)

Post Doctoral Training, 1996-1999, Boston University (Boston, MA)

Instructor, 2000-2003, Massachusetts General Hospital and Harvard Medical School

Research Interests

Molecular ageing of the brain; Alzheimer's disease

Research Overview

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 ageing, and ageing itself is the single most important risk factor for AD. Because of the ongoing increase in life expectancy, by 2050 we can expect approximately 25% of the Western population to be over 65 years of age; one third of them will likely develop AD.

The two main histological hallmarks of AD are (i) the abnormal accumulation of amyloid ß-peptide (Aß) 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.

Aß is a 39 to 43 amino acids peptide proteolytically produced by a much larger precursor, the amyloid precursor protein (APP). Genetic studies suggest that the accumulation of Aß in the brain is an early and necessary step for the pathogenesis of AD. These studies are further supported by biochemical results obtained from cellular and transgenic models of AD. For the generation of Aß, APP is sequentially cleaved at ß and y sites (please, see Fig. 1) through two different biochemical reactions involving a ß-site APP cleaving enzyme (BACE1) and a multimeric protein complex (y-secretase). BACE1 is the rate-limiting enzyme for Aß biogenesis.

The ceramide connection
Our laboratory has recently shown that the lipid ceramide can regulate both APP processing and Aß generation by affecting the molecular stability of BACE1 (The Journal of Biological Chemistry, 2003). Ceramide is a second messenger that regulates many of the biochemical events that occur during both cellular senescence and organismal ageing, therefore providing us with a novel molecular link between normal ageing and one of the events that occur during the pathogenesis of AD. Our current efforts are focused on the identification of the up-stream and down-stream molecules that mediate the ceramide-dependent regulation of Aß generation during ageing.

The cholesterol connection
The last few years have witnessed the emerging of many results implicating cholesterol with the pathogenesis of AD (for more details, see our review in Nature Neuroscience, 2003). Even though many aspects of cholesterol metabolism can be implicated with a complex and heterogeneous disease like AD, we are currently focusing on the mechanisms that regulate intracellular cholesterol distribution. We already know that the equilibrium between free cholesterol and cholesterol ester, which is controlled by the enzyme ACAT (acylCoA:cholesterol acyltransferase), is able to regulate the processing of APP (Nature Cell Biology, 2001). However, ACAT is not the only intracellular cholesterol "regulator". Our current efforts are focused on the identification of additional molecules that can affect APP metabolism through intracellular cholesterol dynamics.

General remarks
Studies from several groups, including ours, are starting to delineate a complex number of biochemical pathways that can affect both Aß biogenesis and the ability of the brain to sustain/ generate synapses. Some of these pathways often interact between each other and are influenced/modulated by ageing itself (Fig. 2). For example, ageing induces a progressive increase of ceramide content in the brain, which in turn can stabilize BACE1 and activate Aß production and secretion. At the same time, ceramide can regulate receptor-mediated uptake of lipoprotein-associated cholesterol and can affect maturation of the sterol regulatory element binding protein (SREBP), therefore influencing cholesterol metabolism and distribution in the brain. Both events control the generation of Aß and the ability of neurons to generate and sustain their synapses. In addition, ageing is also accompanied by progressive oxidation of circulating lipoprotein, which can lead both to intracellular accumulation of enzymatically resistant cholesterol esters, and to changes in cholesterol dynamics. Some of these events may be able to potentiate themselves, becoming difficult to dissect. However, the great challenge ahead of us is the identification of all the molecules and biochemical events that are involved in the above pathways during normal ageing of the brain. Only then we will able to understand how they influence the progression of Alzheimer's disease, and to design specific treatments for the prevention of this devastating form of dementia.

Search for Luigi Puglielli's literature abstracts on PubMed

Work Related Links

Associated Staff