We have previously explored the metabolism of B-amyloid precursor (APP) in a variety of cultured cells models and sought to produce insoluble Beta-amyloid deposits in cultured human neuronal cells. Mutations flanking the Beta-protein domain migrate with familial Alzheimer's Disease (FAD) supporting the hypothesis that accelerate B-amyloid deposition is sufficient to cause AD. APP670/671 mutations markedly accelerate B-protein production, but now FAD APP717 mutations effect APP and Beta-protein metabolism remains controversial; it may result in a greater percentage of longer forms of B-protein. Because it is a critical determinant in aggregation, we will investigate the C-terminus of secreted B. We are developing specific antibody probes to the C- terminus of B to explore this region in experiments with cultured cells with and without the APP717 mutations, and in AD and control CSF and brains available through the ADRC. Unfortunately, APP-like molecules of similar size are detected by many N-terminal APP antibodies and all C- terminal APP antibodies confusing results in most cultured cell systems even if transection are used. Hence, we are using CNS-derived neuroblastoma which lack detectable endogenous APP or APP-like cross- reacting molecules to examine the FAD APP mutations effects and APP metabolism. Secretion of B protein by cultured cells raise a number of issues concerning the metabolism of B-protein in vitro and the relationship of normal B-protein secretion to pathological B-protein deposition. We propose experiments to analyze the cellular pathway involved in B- production using a unique collection of processing mutants and treatment. Because B-degradation may be just as relevant to amyloidosis as production rates, we also design experiments to define the mechanism of B-degradation which is completely unknown. We have detected and propose to identify unknown proteins associated with APP, and may be involved in APP metabolism. Differences in the transport and metabolism of alternatively spliced APP are suggested from experiments with brain and CSF, but have not been shown in cultured cells. APP751, but not APP695 transgenics are reported to make diffuse B deposits. Thus, we also propose to look at B-protein and APP isoform metabolism in polarized APP transfected and parent NT2/D1 derived human neurons. These experiments should have a direct impact on understanding AD pathogenesis.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Specialized Center (P50)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Qian, Winnie; Fischer, Corinne E; Schweizer, Tom A et al. (2018) Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease. Curr Alzheimer Res 15:187-194
Weintraub, Sandra; Besser, Lilah; Dodge, Hiroko H et al. (2018) Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set (UDS). Alzheimer Dis Assoc Disord 32:10-17
Gallagher, Damien; Kiss, Alex; Lanctot, Krista et al. (2018) Depression and Risk of Alzheimer Dementia: A Longitudinal Analysis to Determine Predictors of Increased Risk among Older Adults with Depression. Am J Geriatr Psychiatry 26:819-827
Wilmoth, Kristin; LoBue, Christian; Clem, Matthew A et al. (2018) Consistency of traumatic brain injury reporting in older adults with and without cognitive impairment. Clin Neuropsychol 32:524-529
Haaksma, Miriam L; Calderón-Larrañaga, Amaia; Olde Rikkert, Marcel G M et al. (2018) Cognitive and functional progression in Alzheimer disease: A prediction model of latent classes. Int J Geriatr Psychiatry 33:1057-1064
Ting, Simon Kang Seng; Foo, Heidi; Chia, Pei Shi et al. (2018) Dyslexic Characteristics of Chinese-Speaking Semantic Variant of Primary Progressive Aphasia. J Neuropsychiatry Clin Neurosci 30:31-37
Ramsey, Christine M; Gnjidic, Danijela; Agogo, George O et al. (2018) Longitudinal patterns of potentially inappropriate medication use following incident dementia diagnosis. Alzheimers Dement (N Y) 4:1-10
Saberi, Shahram; Stauffer, Jennifer E; Jiang, Jie et al. (2018) Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis. Acta Neuropathol 135:459-474
Lee, Ming-Hsiang; Siddoway, Benjamin; Kaeser, Gwendolyn E et al. (2018) Somatic APP gene recombination in Alzheimer's disease and normal neurons. Nature 563:639-645
Hadjichrysanthou, Christoforos; McRae-McKee, Kevin; Evans, Stephanie et al. (2018) Potential Factors Associated with Cognitive Improvement of Individuals Diagnosed with Mild Cognitive Impairment or Dementia in Longitudinal Studies. J Alzheimers Dis 66:587-600

Showing the most recent 10 out of 914 publications