Statistical measures for shelf reading in an academic health sciences center library.
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Catalogs, Library↗
Biomedical subjects
W A Pedersen
Publications and source records attributed to W A Pedersen.
Graphing: a tool for collection development.
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Book Collecting↗
Effects of amyloid precursor protein derivatives and oxidative stress on basal forebrain cholinergic systems in Alzheimer's disease.
The dysfunction and degeneration of cholinergic neuronal circuits in the brain is a prominent feature of Alzheimer's disease. Increasing data suggest that age-related oxidative stress contributes to degenerative changes in basal forebrain cholinergic systems. Experimental studies have shown that oxidative stress, and membrane lipid peroxidation in particular, can disrupt muscarinic cholinergic signaling by impairing coupling of receptors to GTP-binding proteins. Altered proteolytic processing of the beta-amyloid precursor protein (APP) may contribute to impaired cholinergic signaling and neuronal degeneration in at least two ways. First, levels of cytotoxic forms of amyloid beta-peptide (A beta) are increased; A beta damages and kills neurons by inducing membrane lipid peroxidation resulting in impairment of ion-motive ATPases, and glucose and glutamate transporters, thereby rendering neurons vulnerable to excitotoxicity. The latter actions of A beta may be mediated by 4-hydroxynonenal, an aldehydic product of membrane lipid peroxidation that covalently modifies and inactivates the various transporter proteins. Subtoxic levels of A beta can also suppress choline acetyltransferase levels, and may thereby promote dysfunction of intact cholinergic circuits. A second way in which altered APP processing may endanger cholinergic neurons is by reducing levels of a secreted form of APP which has been shown to modulate neuronal excitability, and to protect neurons against excitotoxic, metabolic and oxidative insults. Mutations in presenilin genes, which are causally linked to many cases of early-onset inherited Alzheimer's disease, may increase vulnerability of cholinergic neurons to apoptosis. The underlying mechanism appears to involve perturbed calcium regulation in the endoplasmic reticulum, which promotes loss of cellular calcium homeostasis, mitochondrial dysfunction and oxyradical production. Knowledge of the cellular and molecular underpinnings of dysfunction and degeneration of cholinergic circuits is leading to the development of novel preventative and therapeutic approaches for Alzheimer's disease and related disorders.
Acetylcholine↗
Neurodegenerative disorders and ischemic brain diseases.
Degeneration and death of neurons is the fundamental process responsible for the clinical manifestations of many different neurological disorders of aging, incuding Alzheimer's disease, Parkinson's disease and stroke. The death of neurons in such disorders involves apoptotic biochemical cascades involving upstream effectors (Par-4, p53 and pro-apoptotic Bcl-2 family members), mitochondrial alterations and caspase activation. Both genetic and environmental factors, and the aging process itself, contribute to intiation of such neuronal apoptosis. For example, mutations in the amyloid precursor protein and presenilin genes can cause Alzheimer's disease, while head injury is a risk factor for both Alzheimer's and Parkinson's diseases. At the cellular level, neuronal apoptosis in neurodegenerative disorders may be triggered by oxidative stress, metabolic compromise and disruption of calcium homeostasis. Neuroprotective (antiapoptotic) signaling pathways involving neurotrophic factors, cytokines and "conditioning responses" can counteract the effects of aging and genetic predisposition in experimental models of neurodegenerative disorders. A better understanding of the molecular underpinnings of neuronal death is leading directly to novel preventative and therapeutic approaches to neurodegenerative disorders.
Apoptosis↗
Aberrant stress response associated with severe hypoglycemia in a transgenic mouse model of Alzheimer's disease.
Patients with Alzheimer's disease (AD) exhibit alterations in glucose metabolism and dysregulation of the stress-responsive hypothalamic-pituitary-adrenal (HPA) neuroendocrine system. The mechanisms responsible for these alterations and their possible contributions to the neurodegenerative process in AD are unknown. We now report that transgenic mice expressing a mutant form of human amyloid precursor protein (APP) that causes inherited early-onset AD exhibit increased sensitivity to physiological stressors, which is associated with aberrancies in HPA function and regulation of blood glucose levels. Specifically, APP mutant mice exhibit severe hypoglycemia and death following food restriction, and sustained elevations of plasma glucocorticoid levels and hypoglycemia following restraint stress. The alterations in HPA function and glucose regulation were evident in relatively young mice prior to overt deposition of amyloid beta-peptide (A beta). However, diffuse accumulations of A beta were present in the hypothalamus of older mice, suggesting a role for soluble forms of A beta in dysregulation of HPA function. Our data demonstrate disturbances in neuroendocrine function in APP mutant mice similar to those seen in AD patients. These impairments in stress response, glucocorticoid signaling, and regulation of blood glucose should be considered in interpretations of data from past and future studies of APP mutant mice.
Alzheimer Disease↗