Dr. Craig Atwood is an Associate Professor of Medicine at the University of Wisconsin and an investigator with the Geriatric Research, Education and Clinical Center at the William S. Middleton memorial Veterans Administration Hospital in Madison. Dr. Atwood and a colleague (Dr. Richard Bowen) have proposed a novel theory of aging based on the modulation of cell cycle signaling by reproductive hormones. This theory (ÔThe Reproductive-Cell Cycle Theory of AgingÕ) introduces a new definition of aging that has facilitated the conceptualization of why and how we age at the evolutionary, physiological and molecular levels (Bowen and Atwood, 2004). The basic premise behind the research is that hormones that regulate reproduction in mammals act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence. In essence, this theory proposes that reproductive hormones regulate our aging by modulating the life cycle of cells. Importantly, the theory is not simply a philosophical work; it has immediate and practical implications for extending longevity and delaying/preventing age-related diseases as illustrated below.

Dr. Atwood has diverse research interests (see Novel Theories). Below are some of the different research themes ongoing in the laboratory.

1. Hormonal Regulation of AlzheimerÕs Disease The aging theory evolved from my research conducted on how the age-related dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause and during andropause promotes neurodegeneration. From these studies I found that one member of this axis, the gonadotropin luteinizing hormone (LH) which becomes elevated in serum with aging and which accumulates in pyramidal neurons in the AD brain (Bowen et al., 2002), alters amyloid-ß precursor (AßPP) protein processing and increases amyloid-ß generation (Bowen et al., 2004), the major component of amyloid plaques that deposit in the brains of individuals with AD. Our recent research has confirmed this finding in a transgenic mouse model of AD, and additionally demonstrated that GnRH analogues can stabilize cognition (Casadesus et al., 2006). Moreover, neurons in the senescent brain develop other phenotypic characteristics of dividing/transformed cells, such as the expression of LH and osteopontin (Wilson et al., 2006; Wung et al., 2007). From these basic research observations and insights came the basis for the aging theory. Aside from my own research findings, strong support for the theory was recently published by another group in which they show that high levels of a second gonadotropin, follicle-stimulating hormone (FSH), promote osteoporosis, independent of low estrogen levels (Sun et al., 2006; Cell), i.e. FSH, and not estrogens are primarily responsible for osteoporosis. These 2 independent lines of evidence (LH/amyloid production and FSH/osteoclast proliferation) suggest that the surge in gonadotropins following menopause and with andropause is the driving force behind senescent changes seen in aging humans. This research is providing a major paradigm shift in our understanding of senescence.

2. Hormonal Regulation of Aging and Reproduction A second line of research is aimed at defining the exact mechanisms by which reproduction and reproductive hormones regulate aging. In this respect, we recently identified a GnRH receptor orthologue in Caenorhabditis elegans, a model of longevity studies (Vadakkadath Meethal et al., 2006). This is the first report of an evolutionarily conserved GnRH receptor in C. elegans, a central component of the endocrine system that orchestrates reproduction. The identification of an evolutionarily conserved GnRH receptor opens the way to using C. elegans as a model system to study reproductive endocrinology.

3. Autocrine/Paracrine Mechanisms of LH and Neurosteroid Production in the Brain Most recently, I have developed another line of research that is highly integrated with my previously described lines of research. This line of research is based on our recent findings that the production of steroids by neuronal cells in the brain (neurosteroids) is regulated by LH via the regulation of steroidogenic acute regulatory protein expression. This novel finding helps explain for the first time the regulation of steroid synthesis in the brain, important for normal brain function, and how neurosteroid production is altered throughout life and disease (Liu et al., in press). In addition, we have determined that GnRH signals via GnRH receptors present on neurons for the production of LH (Wilson et al., 2006), thereby helping to explain the presence of LH in neurons and itÕs accumulation during AD (Bowen et al., 2002). This is the first time that potential autocrine/paracrine mechanisms of brain hormone production (extra-hypothalamic) have been identified.

4. Amyloid Biology A fourth line of research in my laboratory developed during the last decade has resulted in important discoveries regarding the neurochemical factors that promote the deposition of the amyloid-ß protein. This work evolved from my post-doctoral studies, and I have developed an independent research program that continues to focus on the mechanism of amyloid-ß deposition. This independent work includes identification of the copper binding sites of amyloid-ß both in vivo (Dong et al., 2003) and how this metal ion interaction leads to the oxidative modification of the protein (Atwood et al., 2004). In related studies, we have shown the metal ion chelator/antioxidant, alpha-lipoic acid, stabilizes cognition in a mouse model of AD (Atwood et al., unpublished data), and in collaborative studies (Drs. Veurink and Martins) have demonstrated that the use of combination antioxidant therapies can reverse neurodegeneration in an animal model of protein deposition (Veurink et al., 2002), suggesting a novel antioxidant therapy for AD. Another line of research related to the function of amyloid focuses on the long-standing and very interesting question of whether amyloid-ß is neurotoxic or neurotrophic. Since joining UW, we have demonstrated that amyloid-ß is both; neurotrophic to undifferentiated neurons, but toxic to differentiated neurons via a Cdk5 dependent tau phosphorylation pathway (Liu et al., 2004). In addition, we have found that amyloid-ß production is increased only when neurons commit to death (Verdile et al., in preparation). Further, the physiochemical properties of amyloid-ß indicate it to be a novel vascular sealant that can seal vascular lesions without compromising blood supply to the brain (Atwood et al., 2002a, b; 2003). Thus, amyloid-ß may have as a normal physiological function the repair and growth of neurons during times of neuronal restructuring, i.e. during development, following injury and during senescence. This idea has recently been expounded upon by other AD researchers (Hardy and Cullen, 2006, Nat. Med. 12; 756-7).

5. Hypoxia, and the Metallobiochemistry of the Brain A fifth line of research in my laboratory focuses on the metallobiochemistry of the brain. Our recent studies have indicated that hypoxic conditions promote the redistribution of metal ions in the brain, thereby providing an explanation for the accumulation of metal ions (and the likely source of oxidant stress) in certain neurodegenerative diseases (Bishop et al., submitted). My future studies include identification of the metal ion transport pathways responsible for regulating metal ion influx/efflux in the brain during hypoxia. In this respect, we have shown via microarray analyses that copper alters the expression of key transport proteins in neurons (Chan et al., unpublished data) and that excess copper induces apoptosis of neurons in both in vitro and in vivo models of WilsonÕs disease (Chan et al., 2008).