Alterations in amyloid precursor protein (APP) metabolism, calcium regulation, oxidative metabolism, and transduction systems have been implicated in Alzheimer's disease (AD). Limitations to the use of postmortem brain for examining molecular mechanisms underscore the need to develop a human tissue model representative of the pathophysiological processes that characterize AD. The use of peripheral tissues, particularly of cultured skin fibroblasts derived from AD patients, could complement studies of autopsy samples and provide a useful tool with which to investigate such dynamic processes as signal transduction systems, ionic homeostasis, oxidative metabolism, and APP processing. Peripheral cells as well as body fluids (i.e., plasma and CSF) could also provide peripheral biological markers for the diagnosis of AD. The criteria required for a definite diagnosis of AD presently include clinical criteria in association with histopathologic evidence obtained from biopsy or autopsy. Thus, the use of peripheral markers as a diagnostic tool, either to predict or at least to confirm a diagnosis, may be of great importance.

Abnormalities in calcium regulation, amyloid-beta-protein (A beta) production and oxidative metabolism have been implicated in Alzheimer's disease (AD). The use of cultured fibroblasts complement post-mortem and genetic approaches in clarifying the interaction of these processes and the underlying mechanism for the changes in AD. Definition of gene defects in particular Alzheimer families (FAD) permits elucidation of the role of those genetic abnormalities in altered signal transduction in cell lines from those families. Abnormalities in calcium regulation, ion channels, cyclic AMP, the phosphatidylinositide cascade and oxidative metabolism are well documented in fibroblasts from patients with primary genetic defects in the presenilins. Recent studies in AD fibroblasts that demonstrate abnormal secretion of A beta, a protein known to form the characteristic extracellular amyloid deposits in AD brain, further supports the use of these cells in AD research. Comparison of changes in calcium signaling, mitochondrial oxidation and A beta production in these cells suggests that changes in signal transduction including calcium may be a more consistent observation than altered A beta production in fibroblasts from some FAD families. An understanding of these abnormalities in fibroblasts may provide further insights into the pathophysiology of AD, new diagnostic measures and perhaps innovative therapeutic approaches.

To test whether chromosomal instability is associated with familial Alzheimer's disease, we examined breakage on X chromosomes of fibroblasts derived from patients with familial Alzheimer's disease, using gene cotransfer methodology. The X chromosome is a convenient target for analyzing DNA breakage because of its numerous markers and ease of selection in rodent-human hybrid cells. Patients with familial Alzheimer's disease, including the large Nova Scotia Alzheimer's kindred, show a significantly lower cotransfer of the X-linked glucose-6-phosphate dehydrogenase (G6PD) gene with the selected HPRT gene in hybrid cells, indicating breakage between the markers. Lower cotransfer of the more distant X-linked gene, MIC-2, was statistically significant in this kindred, but not in other patients with familial Alzheimer's disease. The distance between MIC2 and HPRT is sixfold to ninefold greater than that between HPRT and G6PD, suggesting that there may be a "hot spot" for breakage in the latter interval on the X chromosome of patients with familial Alzheimer's disease. The somatic cell hybrid model provides insights into underlying mechanisms for chromosomal breakage induced by the Alzheimer defect. A hypothesis implicating a candidate gene, C1-THF synthase, in the generation of chromosome instability in the pathogenesis of familial Alzheimer's disease, is presented.

Since previous studies suggested that blood choline homeostasis is altered in aging and in Alzheimer's disease, choline uptake was examined in human red blood cells (RBC) from young adults, intellectually-intact elderly controls and outpatients with Alzheimer's disease. Eadie-Hofstee analysis of uptake by RBC from young controls indicated two components; thus, group comparisons were done with 1 and 50 μM choline in the media. Temperature-dependent choline uptake at low and high choline concentrations increased in RBC from elderly controls (62–66%) or Alzheimer patients (52–54%) compared to young controls. These changes in transport were not directly related to altered RBC choline content, since RBC choline concentrations did not vary significantly between groups. However, plasma choline content was significantly elevated in elderly controls and Alzheimer patients compared to young control values. The RBC to plasma ratio of choline was reduced in elderly compared to young controls, whereas the ratio in Alzheimer patients was between the two other groups. Thus, abnormalities in RBC choline uptake and plasma choline content were not exacerbated in Alzheimer patients, and these results do not support suggestions that Alzheimer's disease is a form of generalized accelerated aging. The striking changes in RBC choline uptake and plasma choline content in elderly subjects do indicate age-related changes in systemic choline homeostasis and these abnormalities may contribute to the predisposition of the elderly to neurological diseases.

Annals of the New York Academy of SciencesVolume 378, Issue 1 p. 382-403 THE ROLE OF THE CHOLINERGIC SYSTEM IN THIAMIN DEFICIENCY* Gary Gibson, Gary Gibson Department of Neurology Cornell University Medical College Burke Rehabilitation Center White Plains, New York 10605Search for more papers by this authorLaurie Barclay, Laurie Barclay Department of Neurology Cornell University Medical College Burke Rehabilitation Center White Plains, New York 10605Search for more papers by this authorJohn Blass, John Blass Department of Neurology Cornell University Medical College Burke Rehabilitation Center White Plains, New York 10605Search for more papers by this author Gary Gibson, Gary Gibson Department of Neurology Cornell University Medical College Burke Rehabilitation Center White Plains, New York 10605Search for more papers by this authorLaurie Barclay, Laurie Barclay Department of Neurology Cornell University Medical College Burke Rehabilitation Center White Plains, New York 10605Search for more papers by this authorJohn Blass, John Blass Department of Neurology Cornell University Medical College Burke Rehabilitation Center White Plains, New York 10605Search for more papers by this author First published: March 1982 https://doi.org/10.1111/j.1749-6632.1982.tb31213.xCitations: 57 * Supported by grants NS15125, NS03346, NS16997, AA03883, MH17691, the Winifred Masterson Burke Relief Foundation, and the Will Rogers Institute. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Plum, F. & J. Posner. 1980. The Diagnosis of Stupor and Coma. 3rd edit. F. A. Davis Company. Philadelphia , Pa. Google Scholar 2 Stevens, H. 1937. Avitaminosis B (B1), maze performance and certain aspects of brain chemistry. J. Comp. Psychol. 24: 441458. 10.1037/h0061057 Google Scholar 3 Schade, J. P. & D. H. Ford. 1965. Basic Neurology. pp. 310–320. Elsevier Publ. Co. Netherlands . Google Scholar 4 Perri, V., O. Sacchi & C. Casella. 1970. 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