A neurocomputational model of the role of cholesterol in the development process of Alzheimer's disease

This work presents a mathematical-computational model of the development process of Alzheimer's disease, based on the assumption that cholesterol plays a key role in the formation of hallmark neuropathological lesions that characterize the disease: the senile amyloid plaques and neurofibrillary tangles. The final model, conceived as a system of equations, was implemented as a computer program and, thereafter, two sets of tests were carried out. In the first set of tests, aimed at validating the model, the results obtained from the simulations carried out were qualitatively coherent with in vivo or in vitro experiments found in the consulted literature. In the second set, we performed simulations in order to test a number of hypotheses about the development process of the disease, collected from the literature but yet without experimental confirmation. From the results of these simulations, it was possible to validate those hypotheses and to draw some conclusions about the development process of the disease.

[1]  U. Igbavboa,et al.  Brain membrane cholesterol domains, aging and amyloid beta-peptides , 2002, Neurobiology of Aging.

[2]  J. Kalman,et al.  High cholesterol diet down regulates the activity of activator protein-1 but not nuclear factor-kappa B in rabbit brain. , 2001, Life sciences.

[3]  U. Igbavboa,et al.  Amyloid beta-protein interactions with membranes and cholesterol: causes or casualties of Alzheimer's disease. , 2003, Biochimica et biophysica acta.

[4]  L. Thal,et al.  Cholesterol, oxidative stress, and Alzheimer's disease: expanding the horizons of pathogenesis. , 2002, Free radical biology & medicine.

[5]  W. Banks,et al.  Interactions of β‐Amyloids with the Blood–Brain Barrier , 1997, Annals of the New York Academy of Sciences.

[6]  M. Mercken,et al.  A Cholesterol-Lowering Drug Reduces β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease , 2001, Neurobiology of Disease.

[7]  H. Soininen,et al.  Midlife vascular risk factors and late-life mild cognitive impairment , 2001, Neurology.

[8]  J. Poirier.  Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer's disease. , 2003, Trends in molecular medicine.

[9]  D. Selkoe,et al.  Toward a Comprehensive Theory for Alzheimer's Disease. Hypothesis: Alzheimer's Disease Is Caused by the Cerebral Accumulation and Cytotoxicity of Amyloid β‐Protein , 2000, Annals of the New York Academy of Sciences.

[10]  K. Duff,et al.  Cholesterol in Alzheimer's Disease and Tauopathy , 2002, Annals of the New York Academy of Sciences.

[11]  Y. Kozutsumi,et al.  Interactions of amyloid beta-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. , 2002, Biochemistry.

[12]  K. Yanagisawa.  Cholesterol and pathological processes in Alzheimer's disease , 2002, Journal of neuroscience research.

[13]  D J Stephens,et al.  The role of cholesterol in the biosynthesis of beta-amyloid. , 1999, Neuroreport.

[14]  B. Greenberg,et al.  Modulation of Secreted β-Amyloid Precursor Protein and Amyloid β-Peptide in Brain by Cholesterol* , 1998, The Journal of Biological Chemistry.

[15]  M. Graeber,et al.  Microglial Activation in Alzheimer Disease: Association with APOE Genotype , 1998, Brain pathology.

[16]  E. Mandelkow,et al.  The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer's disease. , 1998, Molecular biology of the cell.

[17]  S. D. Preston,et al.  Cerebrovascular Disease Is a Major Factor in the Failure of Elimination of Aβ from the Aging Human Brain , 2002 .

[18]  M. Tarnawski,et al.  A quantitative immunocytochemical study of the osmotic opening of the blood-brain barrier to endogenous albumin , 1994, Journal of neurocytology.

[19]  A. Koudinov,et al.  The levels of soluble amyloid beta in different high density lipoprotein subfractions distinguish Alzheimer's and normal aging cerebrospinal fluid: implication for brain cholesterol pathology? , 2001, Neuroscience Letters.

[20]  N. Arispe,et al.  Plasma membrane cholesterol controls the cytotoxicity of Alzheimer's disease AβP (1–40) and (1–42) peptides , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  C. Cotman,et al.  Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. , 2004, The Journal of clinical investigation.

[22]  V. Trieu,et al.  Apolipoprotein E and apolipoprotein D expression in a murine model of singlet oxygen-induced cerebral stroke. , 2000, Biochemical and biophysical research communications.

[23]  E. Matsubara,et al.  Isoform‐Specific Effects of Apolipoproteins E2, E3, and E4 on Cerebral Capillary Sequestration and Blood‐Brain Barrier Transport of Circulating Alzheimer's Amyloid β , 1997, Journal of neurochemistry.

[24]  G. Celesia,et al.  Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. , 2000, Archives of neurology.

[25]  R. Neve,et al.  Alzheimer’s disease: a dysfunction of the amyloid precursor protein 1 1 Published on the World Wide Web on 11 September 2000. , 2000, Brain Research.

[26]  M. Mesulam,et al.  A Plasticity‐Based Theory of the Pathogenesis of Alzheimer's Disease , 2000, Annals of the New York Academy of Sciences.

[27]  Rong Wang,et al.  Hypercholesterolemia Accelerates the Alzheimer's Amyloid Pathology in a Transgenic Mouse Model , 2000, Neurobiology of Disease.

[28]  T. Golde,et al.  Cholesterol modulation as an emerging strategy for the treatment of Alzheimer's disease. , 2001, Drug discovery today.

[29]  S. Ji,et al.  Cholesterol Is an Important Factor Affecting the Membrane Insertion of β-Amyloid Peptide (Aβ1–40), Which May Potentially Inhibit the Fibril Formation* , 2002, The Journal of Biological Chemistry.