Faculty Bibliography

OBJECTIVE: Controlling feeding styles in which parents regulate feeding without responding to child cues have been associated with poor self-regulation of feeding and increased weight, but have not been well studied in infancy. We sought to assess maternal perception of infant feeding cues and pressuring feeding styles in an urban Latina Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) population. METHODS: Secondary analysis of a larger study of Latina mothers participating in New York City WIC programs. We examined maternal perception of infant feeding cues and pressuring feeding style. Using logistic regression, we assessed: 1) characteristics associated with perceptions of cues and pressuring to feed, including sociodemographics, breastfeeding, and maternal body mass index; and 2) whether perceptions of cues were associated with pressuring feeding style. RESULTS: We surveyed 368 mothers (84% response rate). Most mothers perceived that babies sense their own satiety. However, 72% believed that infant crying must indicate hunger. Fifty-three percent believed that mothers should always make babies finish the bottle ("pressure to feed"). Pressuring feeding style was associated with foreign maternal country of birth (adjusted odds ratio [AOR] 3.05; 95% confidence interval [CI], 1.66-5.60) and less than a high school education (AOR 1.81; 95% CI, 1.12-2.91). Two perceptions of feeding cues were related to pressuring feeding style: belief that infant crying must indicate hunger (AOR 2.59; 95% CI, 1.52-4.42) and infant hand sucking implies hunger (AOR 1.83; 95% CI, 1.10-3.03). CONCLUSIONS: Maternal characteristics influence perception of infant hunger and satiety. Interpretation of feeding cues is associated with pressuring feeding style. Improving responsiveness to infant cues should be a component of early childhood obesity prevention.

Alzheimer's Disease (AD) is characterized by cerebral accumulation of beta-amyloid peptides (Abeta), which are proteolytically derived from beta-amyloid precursor protein (betaAPP). betaAPP metabolism is highly regulated via various signal transduction systems, e.g., several serine/threonine kinases and phosphatases. Several growth factors known to act via receptor tyrosine kinases also have been demonstrated to regulate sbetaAPP secretion. Among these receptors, insulin and insulin-like growth factor-1 receptors are highly expressed in brain, especially in hippocampus and cortex. Emerging evidence indicates that insulin has important functions in brain regions involved in learning and memory. Here we present evidence that insulin significantly reduces intracellular accumulation of Abeta and that it does so by accelerating betaAPP/Abeta trafficking from the trans-Golgi network, a major cellular site for Abeta generation, to the plasma membrane. Furthermore, insulin increases the extracellular level of Abeta both by promoting its secretion and by inhibiting its degradation via insulin-degrading enzyme. The action of insulin on betaAPP metabolism is mediated via a receptor tyrosine kinase/mitogen-activated protein (MAP) kinase kinase pathway. The results suggest cell biological and signal transduction mechanisms by which insulin modulates betaAPP and Abeta trafficking in neuronal cultures.

Alzheimer's disease (AD) is characterized by the age-related deposition of beta-amyloid (Abeta) 40/42 peptide aggregates in vulnerable brain regions. Multiple levels of evidence implicate a central role for Abeta in the pathophysiology of AD. Abeta peptides are generated by the regulated cleavage of an approximately 700-aa Abeta precursor protein (betaAPP). Full-length betaAPP can undergo proteolytic cleavage either within the Abeta domain to generate secreted sbetaAPPalpha or at the N- and C-terminal domain(s) of Abeta to generate amyloidogenic Abeta peptides. Several epidemiological studies have reported that estrogen replacement therapy protects against the development of AD in postmenopausal women. We previously reported that treating cultured neurons with 17beta-estradiol reduced the secretion of Abeta40/42 peptides, suggesting that estrogen replacement therapy may protect women against the development of AD by regulating betaAPP metabolism. Increasing evidence indicates that testosterone, especially bioavailable testosterone, decreases with age in older men and in postmenopausal women. We report here that treatment with testosterone increases the secretion of the nonamyloidogenic APP fragment, sbetaAPPalpha, and decreases the secretion of Abeta peptides from N2a cells and rat primary cerebrocortical neurons. These results raise the possibility that testosterone supplementation in elderly men may be protective in the treatment of AD.

In molecular neurobiology, perhaps no molecule has been as thoroughly examined as Alzheimer's beta-amyloid precursor protein (beta-APP). In the years since the cDNA encoding beta-APP was cloned, the protein has been the subject of unparalleled scrutiny on all levels. From molecular genetics and cellular biology to neuroanatomy and epidemiology, no scientific discipline has been left unexplored - and with good reason. beta-amyloid (Abeta) is the main constituent of the amyloidogenic plaques which are a primary pathological hallmark of Alzheimer's disease, and bta-APP is the protein from which Abeta is cleaved and released. Unraveling the molecular events underlying Abeta generation has been, and remains, of paramount importance to scientists in our field. In this review we will trace the progress that has been made in understanding the molecular and cellular basis of beta-APP trafficking and processing, or alternatively stated, the molecular basis for Abeta generation. Imperative to a complete understanding of Abeta generation is the delineation of its subcellular localization and the identification of proteins that play either direct or accessory roles in Abeta generation. We will focus on the regulation of beta-APP cleavage through diverse signal transduction mechanisms and discuss possible points of therapeutic intercession in what has been postulated to be a seminal molecular step in the cascade of events terminating in the onset of dementia, loss of neurons, and eventual death from Alzheimer's disease.